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US4647576A - Trans-6-[2-(substitutedpyrrol-1-yl)alkyl]-pyran-2-one inhibitors of cholesterol synthesis - Google Patents

Trans-6-[2-(substitutedpyrrol-1-yl)alkyl]-pyran-2-one inhibitors of cholesterol synthesis Download PDF

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Publication number
US4647576A
US4647576A US06/679,676 US67967684A US4647576A US 4647576 A US4647576 A US 4647576A US 67967684 A US67967684 A US 67967684A US 4647576 A US4647576 A US 4647576A
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Prior art keywords
hydroxy
pyran
ethyl
tetrahydro
pyrrol
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US06/679,676
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Milton L. Hoefle
Bruce D. Roth
Charlotte D. Stratton
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Warner Lambert Co LLC
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Warner Lambert Co LLC
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Priority to US06/679,676 priority Critical patent/US4647576A/en
Priority to KR858501374D priority patent/KR890001449B1/en
Priority to CA000489315A priority patent/CA1242721A/en
Priority to NZ213252A priority patent/NZ213252A/en
Priority to AU46867/85A priority patent/AU573027B2/en
Priority to EP85306382A priority patent/EP0179559A3/en
Priority to ES547055A priority patent/ES8701756A1/en
Priority to GR852297A priority patent/GR852297B/el
Priority to FI853632A priority patent/FI853632L/en
Priority to DK430485A priority patent/DK430485A/en
Priority to KR1019850006950A priority patent/KR890001050B1/en
Priority to NO853725A priority patent/NO853725L/en
Priority to PT81179A priority patent/PT81179B/en
Publication of US4647576A publication Critical patent/US4647576A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • the present invention is related to compounds and pharmaceutical compositions useful as hypocholesterolemic and hypolipidemic agents. More particularly, this invention concerns certain trans-6-[2-(substitutedpyrrol-1-yl)alkyl]-2-ones and the corresponding ring-opened acids derived therefrom which are potent inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), pharmaceutical composition containing such compounds, and a method of lowering blood serum cholesterol levels employing such pharmaceutical compositions.
  • HMG-CoA reductase 3-hydroxy-3-methylglutaryl-coenzyme A reductase
  • High levels of blood cholesterol and blood lipids are conditions which are involved in the onset of arteriosclerosis. It is well known that inhibitors of HMG-CoA reductase are effective in lowering the level of blood plasma cholesterol, especially low density lipoprotein cholesterol (LDL-C), in man (cf. M. S. Brown and J. L. Goldstein, New England Journal of Medicine (1981), 305, No. 9, 515-517). It has now been established that lowering LDL-C levels affords protection from coronary heart disease (cf. Journal of the American Medical Association (1984) 251, No. 3, 351-374).
  • LDL-C low density lipoprotein cholesterol
  • U.S. Pat. Nos. 3,983,140; 4,049,495 and 4,137,322 disclose the fermentative production of a natural product, now called compactin, having an inhibitory effect on cholesterol biosynthesis.
  • Compactin has been shown to have a complex structure which includes a mevalonolactone moiety (Brown et al., J. Chem. Soc. Perkin I, (1976), 1165.
  • trans-6-[2-(substitutedpyrrol-1-yl)alkyl]pyran-2-ones and the corresponding ring-opened hydroxy-acids derived therefrom which are potent inhibitors of cholesterol biosynthesis by virtue of their ability to inhibit the enzyme 3-hydroxy-3-methylglutarylcoenzyme A reductase (HMG-CoA reductase).
  • the present invention provides compounds of structural formula I ##STR1## wherein X is --CH 2 --, --CH 2 CH 2 --, or --CH(CH 3 )CH 2 --.
  • R 1 is 1-naphthyl; 2-naphthyl; cyclohexyl; norbornenyl; phenyl; phenyl substituted by fluorine, chlorine, hydroxy, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoyloxy of from two to eight carbon atoms; 2-, 3-, or 4-pyridinyl; 2-, 3-, or 4-pyridinyl-N-oxide; or ##STR2## where R 5 is alkyl of from one to four carbon atoms and hal - is chloride, bromide, or iodide.
  • R 2 and R 3 are independently hydrogen; chlorine; bromine; cyano; trifluoromethyl; phenyl; alkyl of from one to four carbon atoms; carboalkoxy of from two to eight carbon atoms; --CH 2 OR 6 where R 6 is hydrogen, alkanoyl of from one to six carbon atoms, or where R 2 and R 3 are --CH 2 OCONHR 7 where R 7 is alkyl of from one to six carbon atoms, phenyl, or phenyl substituted with chlorine, bromine, or alkyl of from one to four carbon atoms.
  • R 2 and R 3 may also, when taken together with the carbon atoms to which they are attached, form a ring denoted by ##STR3## where n is three or four; a ring denoted by ##STR4## a ring denoted by ##STR5## where R 8 is hydrogen, alkyl of from one to six carbon atoms, phenyl, or benzyl; or a ring denoted by ##STR6## where R 9 and R 10 are hydrogen, alkyl of from one to four carbon atoms, or benzyl.
  • R 4 is alkyl of from one to four carbon atoms, cyclopropyl, cyclobutyl, or trifluoromethyl.
  • a method of preparing compounds of formula I above by (a) first reacting a substituted [(pyrrol-1-yl)alkyl]aldehyde compound of formula III ##STR8## where X, R 1 , R 2 , R 3 , and R 4 are as defined above, with the alkali metal salt of the dianion of methyl acetoacetate to form a compound of structural formula IV ##STR9## where X, R 1 , R 2 , R 3 , and R 4 are as defined above, then successivly (b) reducing compound IV with a trialkylborane and sodium borohydride and (c) oxidizing with alkaline hydrogen peroxide to produce an acid compound of formula V ##STR10## and finally (d) cyclizing, if desired, the acid compound of formula V to a lactone compound of formula I by heating in an inert solvent or, alternatively converting, if desired, the acid compound of formula V to a pharmaceutical
  • the present invention provides pharmaceutical compositions, useful as hypolipidemic or hypocholesterolemic agents, comprising a hypolipidemic or hypocholesterolemic affective amount of a compound in accordance with this invention as set forth above, in combination with a pharmaceutically acceptable carrier.
  • the present invention provides a method of inhibiting cholesterol biosynthesis in a patient in need of such treatment by administering a pharmaceutical composition in accordance with the present invention as defined above.
  • the present invention provides compounds of formula I above wherein X is --CH 2 CH 2 --, R 1 is as defined above, R 2 and R 3 are independently hydrogen, chlorine, or bromine, and R 4 is as defined above.
  • the present invention provides compounds of formula I above where X is --CH 2 CH 2 --, R 1 is phenyl or phenyl substituted by fluorine, chlorine, hydroxy, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoyloxy of from two to eight carbon atoms, or where R 1 is 2-, 3-, or 4-pyridinyl; 2-, 3-, or 4-pyridinyl-N-oxide, or ##STR11## where R 5 is alkyl of from one to four carbon atoms and hal - is chloride, bromide, or iodide.
  • R 2 and R 3 are preferably independently hydrogen, chlorine, or bromine
  • R 4 is alkyl of from one to four carbon atoms or trifluoromethyl.
  • the present invention provides compounds of formula I above where X is --CH 2 CH 2 --, R 1 is phenyl or phenyl substituted by fluorine, chlorine, hydroxy, trifluoromethyl, alkoxy of from one to four carbon atoms, or alkanoyloxy of from two to eight carbon atoms, R 2 and R 3 are independently hydrogen, chlorine, or bromine, and R 4 is isopropyl or trifluoromethyl.
  • the present invention provides compounds of formula I above where X is --CH 2 CH 2 --, and R 1 is phenyl or phenyl substituted by fluorine, chlorine, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoyloxy of from two to eight carbon atoms, or where R 1 is 1-naphthyl, or 2-naphthyl.
  • R 2 and R 3 are independently hydrogen, chlorine, bromine, cyano, trifluoromethyl, phenyl, alkyl of from one to four carbon atoms, carboalkoxy of from two to eight carbon atoms, --CH 2 OR 6 where R 6 is hydrogen or alkanoyl of from one to six carbon atoms, --CH 2 OCONHR 7 where R 7 is alkyl of from one to six carbon atoms, phenyl, or phenyl substituted with chlorine, bromine, or alkyl of from one to four carbon atoms.
  • R 2 and R 3 may also, when taken together with the carbon atoms to which they are attached, form a ring denoted by ##STR12## where n is three or four; a ring denoted by ##STR13## a ring denoted by ##STR14## where R 8 is hydrogen, alkyl of from one to four carbon atoms, phenyl, or benzyl; or a ring denoted by ##STR15## where R 9 and R 10 are hydrogen, alkyl of from one to four carbon atoms, or benzyl.
  • R 4 is preferably alkyl of from one to four carbon atoms, cyclopropyl, cyclobutyl, or trifluoromethyl.
  • the present invention provides compounds of formula I above where X is --CH 2 CH 2 --, and R 1 is phenyl or phenyl substituted by fluorine, chlorine, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoyloxy of from two to eight carbon atoms.
  • R 2 and R 3 are preferably independently hydrogen, chlorine, bromine, phenyl, or carboalkoxy of from two to eight carbon atoms.
  • R 2 and R 3 may also, when taken together with the carbon atoms to which they are attached, form a ring denoted by ##STR16## where n is three or four; a ring denoted by ##STR17## where R 8 is hydrogen, or alkyl of from one to four carbon atoms; or a ring denoted by ##STR18## where R 9 and R 10 are hydrogen or alkyl of from one to four carbon atoms.
  • R 4 is preferably alkyl of from one to four carbon atoms, or trifluoromethyl.
  • the present invention provides compounds of formula I above where X is --CH 2 CH 2 --, R 1 is is phenyl or phenyl substituted by fluorine, chlorine, trifluormethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoyloxy of from two to eight carbon atoms.
  • R 2 and R 3 are preferably independently carboalkoxy of from two to eight carbon atoms or, when taken together with the carbon atoms to which they are attached form a ring denoted by ##STR19## where R 8 is hydrogen or alkyl of from one to four carbon atoms.
  • R 4 is preferably isopropyl or trifluoromethyl.
  • alkyl denotes a branched or unbranched saturated hydrocarbon group derived by the removal of one hydrogen atom from an alkane.
  • alkoxy denotes an alkyl group, as just defined, attached to the parent molecular residue through an oxygen atom.
  • alkanoyloxy is meant to denote an alkyl group, as defined above, attached to a carbonyl group and thence, through an oxygen atom, to the parent molecular residue.
  • carboalkoxy is meant to denote an alkyl group, as defined above, attached to an oxygen atom and thence, through a carbonyl group, to the parent molecular residue.
  • bornenyl denotes a group derived by the removal of a hydrogen atom (other than at a bridgehead carbon atom) from bicyclo[2.2.1]hept-2-ene.
  • Reaction Sequence 1 Compounds of the present invention where R 2 and R 3 are hydrogen are prepared by the methods outlined in Reaction Sequence 1 or Reaction Sequence 2.
  • Reaction Sequence 1 the aldehydes, VI, are reacted with the appropriately substituted vinylketones, VII, in the presence of the thiazolium salt, VIII, and a base such as triethylamine, to produce the diketones, IX.
  • a base such as triethylamine
  • the diketones, IX are reacted with an omega-aminoalkylnitrile (compound Roman numeral ten where the value of X is methylene, ethylene, or 1-methylethylene) in acetic acid to produce the disubstituted pyrrole nitriles, XI.
  • omega-aminoalkylnitrile compound Roman numeral ten where the value of X is methylene, ethylene, or 1-methylethylene
  • Reaction of the pyrrole aldehydes, XII, with the dilithium or lithium sodium salt methyl acetoacetate produces the 7-(substitutedpyrrolyl)-5-hydroxy-3-oxo-heptanoates, XIII.
  • the heptanoates, XIII are dissolved in a polar solvent such as tetrahydrofuran, through which a small quantity of air has been bubbled.
  • a slight excess of a trialkylborane, such as tributylborane is added to the mixture which is then cooled to a temperature of preferably between about 0° C. and -78° C. after which sodium borohydride is added.
  • the acids may be converted to a corresponding pharmaceutically acceptable salt by conventional methods or, alternatively, cyclized to the 6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-ones, I, by dehydration in an inert solvent such as refluxing toluene with azeotropic removal of water.
  • This cyclization reaction is found to produce material containing from 85-90% of the desired active trans-configuration of the 4-hydroxy group relative to the 6-(substitutedpyrrolyl)alkyl group on the pyran-2-one lactone ring.
  • Reaction Sequence 2 Alternative procedures for preparing compounds of formula I of this invention where R 2 and R 3 are hydrogen, and for preparing intermediates, are illustrated in Reaction Sequence 2.
  • the diketones, IX can be prepared by reacting the known alpha-haloketones, XV, with the sodium salt of known beta-ketoesters, XVI, followed by hydrolysis and decarboxylation in the conventional manner.
  • the diketones, IX are reacted with ammonium acetate in acetic acid to produce the cyclized 2,5-disubstituted pyrroles, XVII. ##STR21##
  • R 1 and/or R 4 are sterically bulky groups, involves reaction of the diketones, IX, with an omega-hydroxyalkyl amine (compound XVIII where X is methylene, ethylene, 1-methylethylene), to produce the N-(omega-hydroxy-alkyl)-2,5-disubstitutedpyrroles, XIX.
  • an omega-hydroxyalkyl amine compound XVIII where X is methylene, ethylene, 1-methylethylene
  • the 2,5-disubstitutedpyrroles, XVII are converted to the omega-(substitutedpyrrolyl)aldehydes, XX, by sequential reaction with sodium hydride, a 1,1-dimethoxy-omega-bromoalkane (compound XXI where X is methylene, ethylene, 1-methylethylene, or vinyl), and then acid.
  • the aldehydes, XX are subsequently used in the preparation of compounds of formula I of this invention as illustrated above in Reaction Sequence 1.
  • the 2,5-disubstituted pyrroles, XVII are converted to the corresponding (2,5-disubstitutedpyrrolyl)nitriles, XXII (when X is ethylene), by reaction with acrylonitrile or, alternatively (when X is other than ethylene), by starting with compounds of formula XIX.
  • the hydroxy functionality of compounds of formula XIX is converted to the p-toluenesulfonate by conventional means, and the tosylate group is subsequently displaced by cyanide ion to produce the nitriles of formula XXII.
  • the compounds of formula XXII are subsequently used in the preparation of compounds of formula I of this invention by methods detailed in Reaction Sequence 1 above.
  • Starting materials and intermediates employed in Reaction Sequences 1 and 2 above may be prepared by the general methods outlined in Reaction Sequence 3.
  • the vinyl ketones, XII are prepared by either of the two methods illustrated.
  • the known acid chlorides, XXIII are reacted with the trimethylsilylethene, XXIV, in the presence of anhydrous aluminum chloride in dichloromethane.
  • the compounds of the present invention where R 2 and R 3 are both halogen can be prepared by the halogenation of the unsubstituted compounds with N-halosuccinimide in a three-step process involving the prior protection of the 4-hydroxy group of the lactone ring.
  • the 2,5-disubstitutedpyrrol-1-yl compounds, XXVII are first converted to the corresponding tert-butyl-dimethylsilyl ethers, XXVIII.
  • the protected compounds and then chlorinated with N-chlorosuccinimide in a polar solvent such as dimethylformamide to produce the silylated 3,4-dichloro compounds, XXIX.
  • the protecting silyl ether group is then subsequently removed by reaction with a buffered fluoride reagent such as tetrabutylammonium fluoride in a mixed acetic acid/tetrahydrofuran solvent system to produce the dichloro compounds, XXX.
  • the (2,5-disubstitutedpyrrol-1-yl)alkyl nitriles, XI are halogenated by employing an N-halosuccinimide in dimethylformamide to provide the 2,5-disubstituted-3,4-dihalopyrroles, XXXI.
  • Reaction Sequence 1 See Aiello, et al., J. Het. Chem., 19: 977 (1982)).
  • These compounds can then be subsequently converted to the compounds of the present invention by conventional methods detailed in Reaction Sequence 1.
  • a third method takes advantage of the chemistry of mesionic compounds of the type described originally by R. Huisgen, et al., Ang. Chem. Int. Ed., 3: 136 (1964).
  • this procedure detailed in Reaction Sequence 6, an ##STR23## N-alkyl-N-acylamino acid is treated with an acid anhydride and a substituted acetylenic compound to produce a pyrrole.
  • Reaction Sequence 6 shows how reaction of an alpha-halo ester, XXXII, with 2-(1-(2-aminoethyl))-1,3-dioxalane in triethylamine provides the N-alkyl-alpha-aminoester, XXXIII.
  • the aminoester, XXXIII is acylated with an acid chloride and subsequently hydrolyzed in base to produce the N-acyl-N-alkyl aminoacid, XXXIV.
  • Reaction of this latter compound with the desired substituted acetylenic compound, XXXV produces the substituted pyrrole compounds, XXXVI.
  • Acidic hydrolysis of XXXVI yields the aldehyde compounds, XXXVII, analogous to compounds XII of Reaction Sequence 1.
  • Compounds of formula XXXVII are used in subsequent steps in a manner detailed in Reaction Sequence 1 to produce compounds of the present invention.
  • Preferred substituents for the substituted acetylenic compounds in this method of making compounds of the present invention include carboalkoxy groups, phenyl groups, alkanoyl groups, alkyl groups and cyano groups.
  • pyrroles can be derived from compounds of the general formula XXXVI when the groups R 2 and R 3 are carbomethoxy. Some of these transformations are detailed in Reaction Sequences 7 and 8. For example, as shown in Reaction Sequence 7, reduction of XXXVI with a reducing agent such as lithium aluminum hydride results in the bis(hydroxymethyl)pyrrole which can be subsequently further reduced to the dimethyl compound,
  • reaction of the compounds of formula XXXVI with a Grignard reagent or an alkyl-lithium reagent in the conventional manner followed by reduction and standard work-up affords the higher dialkylpyrroles, XXXIX.
  • reaction of XXXVI with primary amines followed by thermal cyclization in the conventional manner, provides the pyrrolosuccinimides, XLI, which can be reduced to XLII, if desired by reducing agents such as lithium aluminum hydride.
  • the bis(hydroxymethyl)pyrrole compounds derived from the lithium aluminum hydride reduction of XXXVI can be converted to their corresponding esters or carbamates by reaction with the desired acid anhydride or isocyanate, respectively. (See Anderson, et al., J. Med. Chem., 22: 977 (1979)).
  • the acids, XLIII, derived by convention hydrolysis of compounds of formula XXXVI can also be converted to the bis(amido)pyrroles, XLIV, which in turn can be dehydrated to produce the bis(nitrilo)pyrroles, XLV.
  • the bis(alkanoyl)pyrroles, XLVI can be derived from the bis(nitrilo)pyrroles by reaction in the convention manner with the appropriate Grignard reagents.
  • the ring-opened dihydroxy-acids of structural formula II above are intermediates in the synthesis of the lactone compounds in accordance with the above-detailed reaction methods, or may be produced from the lactone compounds by conventional hydrolysis of the lactone compounds of formula I.
  • compounds of the present invention react to form salts with pharmaceutically acceptable metal and amine cations formed from organic and inorganic bases.
  • pharmaceutically acceptable metal cation contemplates positively charged metal ions derived from sodium, potassium, calcium, magnesium, aluminum, iron, zinc and the like.
  • pharmaceutically acceptable amine cation contemplates the positively charged ions derived from ammonia and organic nitrogenous bases strong enough to form such cations.
  • Bases useful for the formation of pharmaceutically acceptable nontoxic base addition salts of compounds of the present invention form a class whose limits are readily understood by those skilled in the art.
  • the free acid form of the compound may be regenerated from the salt, if desired, by contacting the salt with a dilute aqueous solution of an acid such as hydrochloric acid.
  • the base addition salts may differ from the free acid form of compounds of this invention in such physical characteristics as melting point and solubility in polar solvents, but are considered equivalent to the free acid forms for purposes of this invention.
  • the compounds of this invention can exist in unsolvated as well as solvated forms.
  • the solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, are equivalent to the unsolvated forms for purposes of this invention.
  • the compounds of this invention are useful as hypocholesterolemic or hypolipidemic agents by virtue of their ability to inhibit the biosynthesis of cholesterol through inhibition of the enzyme 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase).
  • HMG-CoA reductase 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase
  • a first method utilized the procedure described by R. E. Dugan et al., Archiv. Biochem. Biophys., (1972), 152, 21-27.
  • the level of HMG-CoA enzyme activity in standard laboratory rats is increased by feeding the rats a chow diet containing 5% cholestyramine for four days, after which the rats are sacrificed.
  • the rat livers are homogenized, and the incorporation of cholesterol- 14 C-acetate into nonsaponifiable lipid by the rat liver homogenate is measured.
  • the micromolar concentration of compound required for 50% inhibition of sterol synthesis over a one-hour period is measured, and expressed as an IC 50 value.
  • a second method employed the procedure detailed by T. Kita, et al., J. Clin. Invest., (1980), 66: 1094-1100.
  • the amount of 14 C-HMG-CoA converted to 14 C-mevalonate in the presence of a purified enzyme preparation of HMG-CoA reductase was measured.
  • the micromolar concentration of compound required for 50% inhibition of cholesterol synthesis was measured and recorded as an IC 50 value.
  • inert, pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersable granules, capsules, cachets, and suppositories.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material.
  • the carrier is a finely divided solid which is in a mixture with finely divided active compound.
  • the active compound is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • a low-melting wax such as a mixture of fatty-acid glycerides and cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds and allowed to cool and solidify.
  • the powders and tablets preferably contain 5 to about 70% of the active ingredient.
  • Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and the like.
  • preparation is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier, which is thus in accordance with it.
  • carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier, which is thus in accordance with it.
  • cachets are included. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.
  • Liquid form preparations include solutions, suspensions, and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection. Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired.
  • Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water with viscous material, i.e., natural or synthetic gums, resins, methyl, cellulose, sodium carboxymethyl cellulose, and other well-known suspending agents.
  • the pharmaceutical preparation is in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, for example, packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can also be a capsule, cachet, or tablet itself or it can be the appropriate number of any of these packaged forms.
  • the compounds utilized in the pharmaceutical method of this invention are administered to the patient at dosage levels of from 40 mg to 600 mg per day. For a normal human adult of approximately 70 kg or body weight, this translates to a dosage of from about 0.5 mg/kg to about 8.0 mg/kg of body weight per day.
  • the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of optimum dosages for a particular situation is within the skill of the art.
  • Step A Preparation of 1-(4-fluorophenyl)-5-methyl-1,4-hexanedione.
  • Isopropyl vinyl ketone (1.97 g, 20 mmol), prepared from isobutyryl chloride and vinyl trimethylsilane in accordance with the method detailed in Tet. Letters, (1979), 1995, was mixed with 4-fluorobenzaldehyde (2.4 g, 20 mmol), 2 ml (14 mmol) of triethylamine, and 1.0 g (4.0 mmol) of 2-(2-hydroxyethyl)-3-methyl-4-benzylthiazolium chloride. The mixture was stirred and heated under nitrogen for five hours. After cooling to room temperature, the mixture was partitioned between ether (200 ml) and water (50 ml).
  • the water layer was extracted with 200 ml of ether and the ether solutions were combined.
  • the combined ether solution was washed successively with 50 ml of water, two 50-ml portions of 2M hydrochloric acid, and 50 ml of brine.
  • the ether solution was dried over anhydrous magnesium sulfate. After removal of the ether, the remaining liquid was flash chromatographed on silica gel eluting with 20:1 (volume/volume) hexane-ethyl acetate. This procedure afforded 2.59 g of pure 1-(4-fluorophenyl)-5-methyl-1,4-hexanedione, mp 47°-49° C.
  • Step B Preparation of 2-[2-[2-(4-fluorophenyl)-5-(1-methylethyl)-5-methyl-1H-pyrrol-1-yl]]-1-cyanoethane.
  • Recrystallization from isopropyl ether provided analytical material of melting point 78°-80° C.
  • Step C Preparation of 3-[2-[2-(4-fluorophenyl)-5-(1-methylethyl)-1H-pyrrol-1-yl]]-1-propanal.
  • the emulsion which resulted was extracted with two 500-ml portions of ether and the combined ether extracts were washed successively with 100 ml of water, two 100-ml portions of sodium bicarbonate solution, and 100 ml of brine, and then dried over anhydrous magnesium sulfate.
  • the ether was removed and the residue was flash chromatographed over silica gel, eluting with 10:1 (volume/volume) hexane-ethyl acetate, yielding pure 3-[2-[2-(4-fluorophenyl)-5-(1-methylethyl)-1H-pyrrol-1-yl]]-1-propanal.
  • Step D Preparation of methyl 7-[2-[2-(4-fluorophenyl)-5-(1-methylethyl)-1H-pyrrol-1-yl]]-5-hydroxy-3-oxo-heptanoate.
  • Step E Preparation of trans-6-[2-[2-(4-fluorophenyl)-5-(1-methylethyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
  • the mixture was then partitioned between 300 ml of water and 300 ml of ether.
  • the ether layer was extracted with 50 ml of 10% sodium hydroxide solution and the water layers were combined, acidified with concentrated hydrochloric acid, and extracted with two 500-ml portions of ethyl acetate.
  • the ethyl acetate extracts were combined, washed twice with brine, and dried over anhydrous magnesium sulfate. Removal of the ethyl acetate yielded 12.5 g of an oily acid which was dissolved in 500 ml of toluene and heated to azeotropically remove water.
  • Example 1 The procedure of Example 1 was employed with the substitution of equimolar amounts of 4-fluorobenzaldehyde and 3-butene-2-one for the 1-(4-fluorophenyl)-2-propene-1-one and isobutyraldehyde in Step A of Example 1. Thereafter, the procedure of Steps B-E were followed to produce trans-6-[2-[2-(4-fluorophenyl)-5-methyl-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
  • Example 1 The procedure of Example 1 was employed with the substitution of equimolar amounts of 4-fluorobenzaldehyde and 1-cyclopropyl-2-propene-1-one for the 1-(4-fluorophenyl)-2-propene-1-one and isobutyraldehyde in Step A of Example 1. Thereafter, the procedure of Steps B-E were followed to produce trans-6-[2-[2-cyclopropyl-5-(4-fluorophenyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
  • Example 1 The procedure of Example 1 was employed with the substitution of equimolar amounts of 4-fluorobenzaldehyde and t-butyl vinyl ketone for the 1-(4-fluorophenyl)-2-propene-1-one and isobutyraldehyde in Step A of Example 1. Thereafter, the procedure of Steps B-E were followed to produce trans-6-[2-[2-(1,1-dimethylethyl)-5-(4-fluorophenyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one, mp 177°-178° C.
  • Example 1 The procedure of Example 1 was employed with the substitution of equimolar amounts of benzaldehyde and 3-butene-2-one for the 1-(4-fluorophenyl)-2-propene-1-one and isobutyraldehyde in Step A of Example 1. Thereafter, the procedure of Steps B-E were followed to produce trans-6-[2-(5-phenyl-2-methyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran2-one, mp 95°-96° C.
  • Example 1 The procedure of Example 1 was employed with the substitution of equimolar amounts of 2-methoxybenzaldehyde and methyl vinyl ketone for the 4-(fluorobenzaldehyde and isopropyl vinyl ketone in Alternate Step A of Example 1. Thereafter, the procedure of Steps B-E were followed to produce trans-tetrahydro-4-hydroxy-6-[2-[2-(2-methoxyphenyl)-5-methyl-1H-pyrrol-1-yl]ethyl]-2H-pyran-2-one, mp 112.5°-113.5° C.
  • Example 1 The procedure of Example 1 was employed with the substitution of equimolar amounts of 4-methoxybenzaldehyde and 3-butene-2-one for the 1-(4-fluorophenyl)-2-propene-1-one and isobutyraldehyde in Step A of Example 1. Therafter, the procedure of Steps B-E were followed to produce trans-tetrahydro-4-hydroxy-6-[2-[2-(4-methoxyphenyl)-5-methyl-1H-pyrrol-1-yl]ethyl]-2H-pyran-2-one, mp 95°-95° C.
  • Example 1 The procedure of Example 1 was employed with the substitution of equimolar amounts of cyclohexanecarboxaldehyde and 3-butene-2-one for the 1-(4-fluorophenyl)-2-propene-1-one and isobutyraldehye in Step A of Example 1. Thereafter, the procedure of Steps B-E were followed to produce trans-6-[2-(2-cyclohexyl-5-methyl-1H-pyrrol-1-yl)ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one, mp 129°-130° C.
  • Example 1 The procedure of Example 1 was employed with the substitution of equimolar amounts of 3-(trifluoromethyl)benzaldehyde and 3-butene-2-one for the 1-(4-fluorophenyl)-2-propene-1-one ad isobutyraldehyde in Step A of Example 1. Thereafter, the procedure of Steps B-E were followed to produce trans-tetrahydro-4-hydroxy-6-[2-[2-methyl-5-[3-(trifluoromethyl)phenyl]-1H-pyrrol-1yl]ethyl]-2H-pyran-2-one.
  • Example 1 The procedure of Example 1 was employed with the substitution of equimolar amounts of 4-phenylbenzaldehyde and 3-butene-2-one for the 1-(4-fluorophenyl)-2-propane-1-one and isobutyraldehyde in Step A of Example 1. Thereafter, the procedure of Steps B-E were followed to produce trans-6-[2-[2-([1,1'-biphenyl]-4-yl)-5-methyl-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one, mp 104°-107° C.
  • Example 1 The procedure of Example 1 was employed with the substitution of equimolar of 1-naphthaldehyde and 3-butene-2-one for the 1-(4-fluorophenyl)-2-propene-1-one and isobutyraldehyde in Step A of Example 1. Thereafter, the procedure of Steps B-E were followed to produce trans-tetrahydro-4-hydroxy-6-[2-[2-methyl-5-(1-naphthalenyl)-1H-pyrrol-1-yl]ethyl]-2H-pyran-2-one, mp 137°-138° C.
  • Example 1 The procedure of Example 1 was employed with the substitution of equimolar amounts of 2-naphthaldehyde and 3-butene-2-one for the 1-(4-fluorophenyl)-2-propene-1-one and isobutyraldehyde in Step A of Example 1. Thereafter, the procedure of Steps B-E were followed to produce trans-tetrahydro-4-hydroxy-6-[2-[2-methyl-5-(2-naphthalenyl)-1H-pyrrol-1-yl]ethyl]-2H-pyran-2-one, mp 45°-50° C.
  • Example 1 The procedure of Example 1 was employed with the substitution of equimolar amounts of bicyclo [2.2.1]hept-5-ene-2-carboxyaldehyde (mixture of diastereomers) and 3-butene-2-one for the 1-(4-fluorophenyl)-2-propene-1-one and isobutyraldehyde in Step A of Example 1.
  • Steps B-E were followed to produce trans-6-[2-(2-bicyclo[2.2.1]hept-5-en-2-yl-5-methyl-1H-pyrrol-1-yl)ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one as a 1:1 mixture of the ando- and exoisomers at the norbornene ring, mp 125°-126° C.
  • Example 1 The procedure of Example 1 was employed with the substitution of equimolar amounts of diphenylacetaldehyde and 3-butene-2-one for the 1-(4-fluorophenyl)-2-propene-1-one and isobutyraldehyde in Step A of Example 1. Thereafter, the procedure of Steps B-E were followed to produce trans-6-[2-[2-diphenylmethyl)-5-methyl-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one, mp 129°-132° C.
  • Example 1 The procedure of Example 1 was employed with the substitution in Step B of 2-aminopropanol in place of the ethanolamine. Therafter, the procedure of Steps C-E were followed to produce trans-6-[2-[2-(4-fluorophenyl)-5-(1-methylethyl)-1H-pyrrol-1-yl]propyl]tetrahydro-4-hydroxy-2H-pyran-2-one, mp 167°-169° C.
  • Example 1 The procedure of Example 1 was employed with the substitution of equimolar amounts of 2-methoxybenzaldehyde and 3-butene-2-one for the 1-(4-fluorophenyl)-2-propene-1-one and isobutyraldehyde in Step A of Example 1. Thereafter, the procedure of Steps B-E were followed to produce trans-tetrahydro-4-hydroxy-6-2-[2-(2-methoxyphenyl)-5-(1-methylethyl)-1H-pyrrol-1-yl-ethyl]-2H-pyran-2-one.
  • Step A Preparation of 6-[2-[2-(4-fluorophenyl)-5(1-methylethyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-tert-butyl dimethylsilyloxy-,trans-2H-pyran-2-one.
  • Step B Preparation of 6-[2-[2-(4-fluorophenyl)-3,4-dichloro-5-(1-methylethyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-trans-2H-pyran-2-one.
  • N-Chlorosuccinimide (6.48 mmoles, 0.87 g) was added in one portion to a stirred solution of 6-[2-[2-(4-fluorophenyl)-5-(1-methylethyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-tert-butyldimethylsilyloxy-trans-2H-pyran-2-one (1.49 g, 3.24 mmoles) in dry DMF (10 ml) cooled to 0° C. under dry nitrogen. The solution was stirred for one hour at 0° C. then warmed to room temperature for three hours. It was then diluted with water (50 ml) and extracted with ether (2 ⁇ 1000 ml).
  • the ether extracts were diluted with 100 ml of hexane and washed with water (50 ml), 10% aq. NaHCO 3 (50 ml), 10% aq. NaHSO 3 (50 ml), brine (50 ml), and dried (MgSO 4 ).
  • the crude product which remained after filtration and concentration was dissolved in tetrahydrofuran (15 ml) and treated with glacial acetic acid (0.75 ml, 13 mmoles) and tetrabutyl ammonium fluoride (9.72 ml of 1M THF solution). The solution was stirred for five hours, diluted with ethyl acetate (100 ml) and washed with saturated aq.
  • Step A Preparation of 2-(4-fluorophenyl)-5-(1-methylethyl)-3,4-dichloro-1H-pyrrole-1-propanenitrile.
  • N-Chlorosuccininide (practical, 105 g, 786.5 mmoles) was added in one portion to a stirred solution of 2-(4-fluorophenyl)-5-(1-methylethyl)-1H-pyrrole-1-propanenitrile (84 g, 327.7 mmoles) in 500 ml of dry dimethylformamide cooled to 0° C. under nitrogen. After stirring for 60 minutes at 0° C. and 90 minutes at 25° C., a further 8 g (60 mmoles) of N-chlorosuccininide were added.
  • Step A Preparation of ethyl-2(1-(1-oxo-2,2,2-trifluoroethyl))-4-oxo-4-(4-fluorophenyl)-butyrate
  • Step B Preparation of 2-(4-fluorophenyl)-5-trifluoromethyl-1H-pyrrole-1-propanenitrile.

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Abstract

6-[2-(Substituted-pyrrol-1-yl)alkyl]pyran-2-ones and the corresponding ring-opened hydroxy-acids derived therefrom are potent inhibitors of the enzyme 3-hydroxy-3-methylglutarylcoenzyme A reductase (HMG-CoA reductase), and are thus useful hypolipidemic and hypocholesterolemic agents. Pharmaceutical compositions containing such compounds, and a method of treatment employing such pharmaceutical compositions are also disclosed.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation-in-part of copending application Ser. No. 653,798 filed Sept. 24, 1984 abandoned.
BACKGROUND OF THE INVENTION
The present invention is related to compounds and pharmaceutical compositions useful as hypocholesterolemic and hypolipidemic agents. More particularly, this invention concerns certain trans-6-[2-(substitutedpyrrol-1-yl)alkyl]-2-ones and the corresponding ring-opened acids derived therefrom which are potent inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), pharmaceutical composition containing such compounds, and a method of lowering blood serum cholesterol levels employing such pharmaceutical compositions.
High levels of blood cholesterol and blood lipids are conditions which are involved in the onset of arteriosclerosis. It is well known that inhibitors of HMG-CoA reductase are effective in lowering the level of blood plasma cholesterol, especially low density lipoprotein cholesterol (LDL-C), in man (cf. M. S. Brown and J. L. Goldstein, New England Journal of Medicine (1981), 305, No. 9, 515-517). It has now been established that lowering LDL-C levels affords protection from coronary heart disease (cf. Journal of the American Medical Association (1984) 251, No. 3, 351-374).
Moreover, it is known that certain derivatives of mevalonic acid (3,5-dihydroxy-3-methylpentanoic acid) and the corresponding ring-closed lactone form, mevalonolactone, inhibit the biosynthesis of cholesterol (cf. F. M. Singer et al., Proc. Soc. Exper. Biol. Med. (1959), 102, 270) and F. H. Hulcher, Arch. Biochem. Biophys. (1971), 146, 422.
U.S. Pat. Nos. 3,983,140; 4,049,495 and 4,137,322 disclose the fermentative production of a natural product, now called compactin, having an inhibitory effect on cholesterol biosynthesis. Compactin has been shown to have a complex structure which includes a mevalonolactone moiety (Brown et al., J. Chem. Soc. Perkin I, (1976), 1165.
U.S. Pat. No. 4,255,444 to Oka et al. discloses several synthetic derivatives of mevalonolactone having antilipidemic activity.
U.S. Pat. Nos. 4,198,425 and 4,262,013 to Mitsue et al. disclose aralkyl derivatives of mevalonolactone which are useful in the treatment of hyperlipidemia.
U.S. Pat. No. 4,375,475 to Willard et al. discloses certain substituted 4-hydroxytetrahydropyran-2-ones which, in the 4(R)-trans stereoisomeric form, are inhibitors of cholesterol biosynthesis.
SUMMARY OF THE INVENTION
In accordance with the present invention, there are provided certain trans-6-[2-(substitutedpyrrol-1-yl)alkyl]pyran-2-ones and the corresponding ring-opened hydroxy-acids derived therefrom which are potent inhibitors of cholesterol biosynthesis by virtue of their ability to inhibit the enzyme 3-hydroxy-3-methylglutarylcoenzyme A reductase (HMG-CoA reductase).
In particular, in its broadest chemical compound aspect, the present invention provides compounds of structural formula I ##STR1## wherein X is --CH2 --, --CH2 CH2 --, or --CH(CH3)CH2 --. R1 is 1-naphthyl; 2-naphthyl; cyclohexyl; norbornenyl; phenyl; phenyl substituted by fluorine, chlorine, hydroxy, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoyloxy of from two to eight carbon atoms; 2-, 3-, or 4-pyridinyl; 2-, 3-, or 4-pyridinyl-N-oxide; or ##STR2## where R5 is alkyl of from one to four carbon atoms and hal- is chloride, bromide, or iodide. R2 and R3 are independently hydrogen; chlorine; bromine; cyano; trifluoromethyl; phenyl; alkyl of from one to four carbon atoms; carboalkoxy of from two to eight carbon atoms; --CH2 OR6 where R6 is hydrogen, alkanoyl of from one to six carbon atoms, or where R2 and R3 are --CH2 OCONHR7 where R7 is alkyl of from one to six carbon atoms, phenyl, or phenyl substituted with chlorine, bromine, or alkyl of from one to four carbon atoms. R2 and R3 may also, when taken together with the carbon atoms to which they are attached, form a ring denoted by ##STR3## where n is three or four; a ring denoted by ##STR4## a ring denoted by ##STR5## where R8 is hydrogen, alkyl of from one to six carbon atoms, phenyl, or benzyl; or a ring denoted by ##STR6## where R9 and R10 are hydrogen, alkyl of from one to four carbon atoms, or benzyl.
R4 is alkyl of from one to four carbon atoms, cyclopropyl, cyclobutyl, or trifluoromethyl.
Also contemplated as falling within this aspect of the invention are the corresponding dihydroxy-acid compounds of formula II corresponding to the opened form of the lactone ring of compounds of formula I ##STR7## where X, R1, R2, R3, and R4 are as defined above, and the pharmaceutically acceptable salts thereof, all of the compounds being in the trans racemate of the tetrahydropyran moiety.
In another aspect of the present invention, there is provided a method of preparing compounds of formula I above by (a) first reacting a substituted [(pyrrol-1-yl)alkyl]aldehyde compound of formula III ##STR8## where X, R1, R2, R3, and R4 are as defined above, with the alkali metal salt of the dianion of methyl acetoacetate to form a compound of structural formula IV ##STR9## where X, R1, R2, R3, and R4 are as defined above, then successivly (b) reducing compound IV with a trialkylborane and sodium borohydride and (c) oxidizing with alkaline hydrogen peroxide to produce an acid compound of formula V ##STR10## and finally (d) cyclizing, if desired, the acid compound of formula V to a lactone compound of formula I by heating in an inert solvent or, alternatively converting, if desired, the acid compound of formula V to a pharmaceutically acceptable salt.
In another aspect, the present invention provides pharmaceutical compositions, useful as hypolipidemic or hypocholesterolemic agents, comprising a hypolipidemic or hypocholesterolemic affective amount of a compound in accordance with this invention as set forth above, in combination with a pharmaceutically acceptable carrier.
In another aspect, the present invention provides a method of inhibiting cholesterol biosynthesis in a patient in need of such treatment by administering a pharmaceutical composition in accordance with the present invention as defined above.
DETAILED DESCRIPTION
In a first preferred subgeneric chemical compound aspect, the present invention provides compounds of formula I above wherein X is --CH2 CH2 --, R1 is as defined above, R2 and R3 are independently hydrogen, chlorine, or bromine, and R4 is as defined above.
In a second preferred subgeneric chemical compound aspect, the present invention provides compounds of formula I above where X is --CH2 CH2 --, R1 is phenyl or phenyl substituted by fluorine, chlorine, hydroxy, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoyloxy of from two to eight carbon atoms, or where R1 is 2-, 3-, or 4-pyridinyl; 2-, 3-, or 4-pyridinyl-N-oxide, or ##STR11## where R5 is alkyl of from one to four carbon atoms and hal- is chloride, bromide, or iodide. In this aspect of the invention, R2 and R3 are preferably independently hydrogen, chlorine, or bromine, and R4 is alkyl of from one to four carbon atoms or trifluoromethyl.
In a third preferred subgeneric chemical compound aspect, the present invention provides compounds of formula I above where X is --CH2 CH2 --, R1 is phenyl or phenyl substituted by fluorine, chlorine, hydroxy, trifluoromethyl, alkoxy of from one to four carbon atoms, or alkanoyloxy of from two to eight carbon atoms, R2 and R3 are independently hydrogen, chlorine, or bromine, and R4 is isopropyl or trifluoromethyl.
In a fourth preferred subgeneric chemical compound aspect, the present invention provides compounds of formula I above where X is --CH2 CH2 --, and R1 is phenyl or phenyl substituted by fluorine, chlorine, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoyloxy of from two to eight carbon atoms, or where R1 is 1-naphthyl, or 2-naphthyl. In this preferred aspect of the invention, R2 and R3 are independently hydrogen, chlorine, bromine, cyano, trifluoromethyl, phenyl, alkyl of from one to four carbon atoms, carboalkoxy of from two to eight carbon atoms, --CH2 OR6 where R6 is hydrogen or alkanoyl of from one to six carbon atoms, --CH2 OCONHR7 where R7 is alkyl of from one to six carbon atoms, phenyl, or phenyl substituted with chlorine, bromine, or alkyl of from one to four carbon atoms. In this aspect of the invention, R2 and R3 may also, when taken together with the carbon atoms to which they are attached, form a ring denoted by ##STR12## where n is three or four; a ring denoted by ##STR13## a ring denoted by ##STR14## where R8 is hydrogen, alkyl of from one to four carbon atoms, phenyl, or benzyl; or a ring denoted by ##STR15## where R9 and R10 are hydrogen, alkyl of from one to four carbon atoms, or benzyl. In this aspect of the invention, R4 is preferably alkyl of from one to four carbon atoms, cyclopropyl, cyclobutyl, or trifluoromethyl.
In a fifth preferred subgeneric chemical compound aspect, the present invention provides compounds of formula I above where X is --CH2 CH2 --, and R1 is phenyl or phenyl substituted by fluorine, chlorine, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoyloxy of from two to eight carbon atoms. R2 and R3 are preferably independently hydrogen, chlorine, bromine, phenyl, or carboalkoxy of from two to eight carbon atoms. In this aspect of the invention R2 and R3 may also, when taken together with the carbon atoms to which they are attached, form a ring denoted by ##STR16## where n is three or four; a ring denoted by ##STR17## where R8 is hydrogen, or alkyl of from one to four carbon atoms; or a ring denoted by ##STR18## where R9 and R10 are hydrogen or alkyl of from one to four carbon atoms. In this aspect of the invention, R4 is preferably alkyl of from one to four carbon atoms, or trifluoromethyl.
In a sixth preferred subgeneric chemical compound aspect, the present invention provides compounds of formula I above where X is --CH2 CH2 --, R1 is is phenyl or phenyl substituted by fluorine, chlorine, trifluormethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoyloxy of from two to eight carbon atoms. R2 and R3 are preferably independently carboalkoxy of from two to eight carbon atoms or, when taken together with the carbon atoms to which they are attached form a ring denoted by ##STR19## where R8 is hydrogen or alkyl of from one to four carbon atoms. In this aspect of the invention, R4 is preferably isopropyl or trifluoromethyl.
As used throughout this specification and the appended claims, the term "alkyl" denotes a branched or unbranched saturated hydrocarbon group derived by the removal of one hydrogen atom from an alkane.
The term "alkoxy" denotes an alkyl group, as just defined, attached to the parent molecular residue through an oxygen atom.
The term "alkanoyloxy" is meant to denote an alkyl group, as defined above, attached to a carbonyl group and thence, through an oxygen atom, to the parent molecular residue.
The term "carboalkoxy" is meant to denote an alkyl group, as defined above, attached to an oxygen atom and thence, through a carbonyl group, to the parent molecular residue.
The term "norbornenyl" denotes a group derived by the removal of a hydrogen atom (other than at a bridgehead carbon atom) from bicyclo[2.2.1]hept-2-ene.
Specific examples of compounds contemplated as falling within the scope of the present invention include the following:
trans-6-[2-[2-Cyclobutyl-5-(4-fluorophenyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
trans-6-[2-[2-Cyclohexyl-5-(4-fluorophenyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-pyran-2-one.
trans-Tetrahydro-4-hydroxy-6-[2-(2-methyl-5-phenyl-1H-pyrrol-1-yl)ethyl]-2H-pyran-2-one.
trans-6-[2-[2-(4-Chlorophenyl)-5-methyl-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
trans-Tetrahydro-4-hydroxy-6-[2-[2-(4-methoxyphenyl)-5-methyl-1H-pyrrol-1-yl]ethyl]-2H-pyran-2-one.
trans-6-[2-[2-([1,1'-Biphenyl]-4-yl)-5-methyl-1H-pyrrol-1-yl)ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
trans-Tetrahydro-4-hydroxy-6-[2-[2-methyl-5-[3-(trifluoromethyl)phenyl]-1H-pyrrol-1-yl]ethyl]-2H-pyran-2-one.
trans-6-[2-[2-(2,5-Dimethylphenyl)-5-(1-methylethyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
trans-6-[2-[2-(2,6-Dimethoxyphenyl)-5-(1-methylethyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
trans-Tetrahydro-4-hydroxy-6-[2-[2-methyl-5-(2-naphthalenyl)-1H-pyrrol-1-yl]ethyl]-2H-pyran-2-one.
trans-6-[2-(2-(Cyclohexyl-5-trifluoromethyl-1H-pyrrol-1-yl)ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
trans-6-[2-[2-(4-Fluorophenyl)-3,4-dimethyl-5-(1-methylethyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
trans-2-(4-Fluorophenyl)-5-(1-methylethyl)-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3,5-dicarboxylic acid.
trans-2-(4-Fluorophenyl)-N3,N3,N4,N4 -tetramethyl-5-(1-methylethyl)-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3,4-dicarboxamide.
trans-6-[2-[3,4-Dichloro-2-(3-fluorophenyl)-5-(1-methylethyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
trans-2-(4-Fluorophenyl)-5-(1-methylethyl)-1-[2-(tetrahydro)-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3,4-dicarbonitrile.
trans-6-[2-[3,4-Diacetyl-2-(4-fluorophenyl)-5-(1-methylethyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
trans-Diethyl 2-(4-Fluorophenyl)-1-[2-(tetrahydro)-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-5-(trifluoromethyl)-1H-pyrrole-3,4-dicarboxylate.
trans-Bis(1-methylethyl) 2-(4-Fluorophenyl)-5-(1-methylethyl)-1-[2-(tetrahydro)-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3,4-dicarboxylate.
trans-6-[2-[3,4-Diethyl-2-(4-fluorophenyl)-5-(1-methylethyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
trans-6-[2-[2-(4-Fluorophenyl)-3,4-bis(hydroxymethyl)-5-(1-methylethyl)-1H-pyrrol-1-yl]-ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
trans-1-Methylethyl 4-Chloro-2-(4-fluorophenyl)-5-(1-methylethyl)-1-[2-(tetrahydro)-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxylate.
trans-6-[2-[4-(4-Fluorophenyl)-6-(1-methylethyl)-1H-furo[3,4-c]pyrrol-5(3H)-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
trans-6-[2-[2-(4-Fluorophenyl)-5-(1-methylethyl)-3,4-bis[[[(phenylamino)carbonyl]oxy]methyl]-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
trans-1-Methylethyl 4-Chloro-5-(4-fluorophenyl)-2-(1-methylethyl)-1-[2-(tetrahydro)-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxylate.
trans-Ethyl 5-(4-Fluorophenyl)-1-[2-(tetrahydro)-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-2-(trifluoromethyl)-1H-pyrrole-3-carboxylate.
trans-Ethyl 5-(4-Fluorophenyl)-2-(1-methylethyl)-4-phenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxylate.
trans-6-[2-[1-(4-Fluorophenyl)-4,5,6,7-tetrahydro-3-methyl-2H-isoindol-2-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
trans-4-(4-Fluorophenyl)-2-methyl-6-(1-methylethyl)-5-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-pyrrolo[3,4-c]pyrrole-1,3(2H,5H)-dione.
trans-6-[2-[1-(4-Fluorophenyl)-5,6-dihydro-3-(1-methylethyl)pyrrolo[3,4-c]pyrrol-2(4H)-yl]ethyl]-tetrahydro-4-hydroxy-2H-pyran-2-one.
trans-6-[2-[1-(4-Fluorophenyl)-5,6-dihydro-5-methyl-3-(1-methylethyl)pyrrolo[3,4-c]pyrrol-2(4H)-yl]-ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
trans-6-[2-[3-Chloro-5-(4-fluorophenyl)-2-(1-methylethyl)-4-phenyl-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
trans-6-[2-[2-(4-Fluorophenyl)-5-(1-methylethyl)-3,4-diphenyl-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
Particularly preferred compounds in accordance with the present invention are:
trans-6-[2-[3,4-Dichloro-2-(4-fluorophenyl)-5-(1-methylethyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
trans-6-[2-[3,4-Dibromo-2-(4-fluorophenyl)-5-(1-methylethyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
trans-6-[2-[2-(4-Fluorophenyl)-5-(trifluoromethyl)-1H-pyrrol-1-yl)ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
trans-Dimethyl 2-(4-Fluorophenyl)-5-(1-methylethyl)-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3,4-dicarboxylate.
trans-6-[2-[2-(4-Fluorophenyl-5-methyl-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
trans-6-[2-[2-(4-Fluorophenyl-5-(1-methylethyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
trans-6-[2-[2-Cyclopropyl-5-(4-fluorophenyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
trans-6-[2-[2-(1,1-Dimethylethyl)-5-(4-fluorophenyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
trans-Tetrahydro-4-hydroxy-6-[2-[2-(2-methoxy-phenyl)-5-trifluoromethyl-1H-pyrrol-1-yl]ethyl]-2H-2-one.
trans-Tetrahydro-4-hydroxy-6-[2-[2-(2-methoxy-phenyl)-5-(1-methylethyl)-1H-pyrrol-1-yl]ethyl]-2H-pyran-2-one.
trans-Tetrahydro-4-hydroxy-6-[2-[2-methyl-5-(1-naphthalenyl)-1H-pyrrol-1-yl]ethyl]-2H-pyran-2-one.
trans-6-[2-(2-Bicyclo[2.2.1]hep-5-en-2-yl-5-methyl-1H-pyrrol-1-yl)ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
trans-6-[2-[2-(4-Fluorophenyl)-5-(1-methylphenyl)-1H-pyrrol-1-yl]propyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
Compounds of the present invention where R2 and R3 are hydrogen are prepared by the methods outlined in Reaction Sequence 1 or Reaction Sequence 2. As shown in Reaction Sequence 1, the aldehydes, VI, are reacted with the appropriately substituted vinylketones, VII, in the presence of the thiazolium salt, VIII, and a base such as triethylamine, to produce the diketones, IX. (See Ang. Chem. Int. Ed., 15: 639-712 (1976)).
The diketones, IX, are reacted with an omega-aminoalkylnitrile (compound Roman numeral ten where the value of X is methylene, ethylene, or 1-methylethylene) in acetic acid to produce the disubstituted pyrrole nitriles, XI.
Treatment of the pyrrole nitriles, XI, with diisobutylaluminum hydride in an inert solvent such as dichloromethane produces the corresponding pyrrole aldehydes, XII. ##STR20##
Reaction of the pyrrole aldehydes, XII, with the dilithium or lithium sodium salt methyl acetoacetate produces the 7-(substitutedpyrrolyl)-5-hydroxy-3-oxo-heptanoates, XIII. The heptanoates, XIII, are dissolved in a polar solvent such as tetrahydrofuran, through which a small quantity of air has been bubbled. A slight excess of a trialkylborane, such as tributylborane, is added to the mixture which is then cooled to a temperature of preferably between about 0° C. and -78° C. after which sodium borohydride is added.
After stirring this mixture for about one to two hours, the mixture is oxidized with basic hydrogen peroxide. The reaction produces the 7-(substituted-pyrrolyl)-3,5-dihydroxyheptanoic acids, XIV, in which the product contains a predominance of the desired R*, R* configuration at carbon atoms three and five which bear the hydroxy groups.
The acids may be converted to a corresponding pharmaceutically acceptable salt by conventional methods or, alternatively, cyclized to the 6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-ones, I, by dehydration in an inert solvent such as refluxing toluene with azeotropic removal of water. This cyclization reaction is found to produce material containing from 85-90% of the desired active trans-configuration of the 4-hydroxy group relative to the 6-(substitutedpyrrolyl)alkyl group on the pyran-2-one lactone ring.
Alternative procedures for preparing compounds of formula I of this invention where R2 and R3 are hydrogen, and for preparing intermediates, are illustrated in Reaction Sequence 2. As shown in Reaction Sequence 2, the diketones, IX, can be prepared by reacting the known alpha-haloketones, XV, with the sodium salt of known beta-ketoesters, XVI, followed by hydrolysis and decarboxylation in the conventional manner. The diketones, IX, are reacted with ammonium acetate in acetic acid to produce the cyclized 2,5-disubstituted pyrroles, XVII. ##STR21##
An alternative for this step, preferred when R1 and/or R4 are sterically bulky groups, involves reaction of the diketones, IX, with an omega-hydroxyalkyl amine (compound XVIII where X is methylene, ethylene, 1-methylethylene), to produce the N-(omega-hydroxy-alkyl)-2,5-disubstitutedpyrroles, XIX.
The 2,5-disubstitutedpyrroles, XVII, are converted to the omega-(substitutedpyrrolyl)aldehydes, XX, by sequential reaction with sodium hydride, a 1,1-dimethoxy-omega-bromoalkane (compound XXI where X is methylene, ethylene, 1-methylethylene, or vinyl), and then acid. The aldehydes, XX, are subsequently used in the preparation of compounds of formula I of this invention as illustrated above in Reaction Sequence 1.
The 2,5-disubstituted pyrroles, XVII, are converted to the corresponding (2,5-disubstitutedpyrrolyl)nitriles, XXII (when X is ethylene), by reaction with acrylonitrile or, alternatively (when X is other than ethylene), by starting with compounds of formula XIX. In this latter instance, the hydroxy functionality of compounds of formula XIX is converted to the p-toluenesulfonate by conventional means, and the tosylate group is subsequently displaced by cyanide ion to produce the nitriles of formula XXII. The compounds of formula XXII are subsequently used in the preparation of compounds of formula I of this invention by methods detailed in Reaction Sequence 1 above.
Starting materials and intermediates employed in Reaction Sequences 1 and 2 above may be prepared by the general methods outlined in Reaction Sequence 3. For example, as shown there, the vinyl ketones, XII, are prepared by either of the two methods illustrated. In one method, the known acid chlorides, XXIII, are reacted with the trimethylsilylethene, XXIV, in the presence of anhydrous aluminum chloride in dichloromethane.
In the alternative method of preparing the vinyl ketones, VII, which is preferred when R1 is an aromatic substituent such as phenyl or substituted phenyl, the
REACTION SEQUENCE 3 ##STR22## known methyl aryl ketones, XXV, are converted to (dimethylaminoethyl)aryl ketones, XXVI, and then by deamination to the vinyl ketones, VII.
The compounds of the present invention of formula I where the groups R2 and R3 are other than hydrogen or halogen can be synthesized by the methods detailed in Reaction Sequences 4-8.
Employing the method detailed in Reaction Sequence 4 the compounds of the present invention where R2 and R3 are both halogen can be prepared by the halogenation of the unsubstituted compounds with N-halosuccinimide in a three-step process involving the prior protection of the 4-hydroxy group of the lactone ring. Thus, for example, the 2,5-disubstitutedpyrrol-1-yl compounds, XXVII, are first converted to the corresponding tert-butyl-dimethylsilyl ethers, XXVIII. The protected compounds and then chlorinated with N-chlorosuccinimide in a polar solvent such as dimethylformamide to produce the silylated 3,4-dichloro compounds, XXIX. The protecting silyl ether group is then subsequently removed by reaction with a buffered fluoride reagent such as tetrabutylammonium fluoride in a mixed acetic acid/tetrahydrofuran solvent system to produce the dichloro compounds, XXX.
Alternatively, as detailed in Reaction Sequence 5, the (2,5-disubstitutedpyrrol-1-yl)alkyl nitriles, XI (see Reaction Sequence 1) are halogenated by employing an N-halosuccinimide in dimethylformamide to provide the 2,5-disubstituted-3,4-dihalopyrroles, XXXI. (See Aiello, et al., J. Het. Chem., 19: 977 (1982)). These compounds can then be subsequently converted to the compounds of the present invention by conventional methods detailed in Reaction Sequence 1.
A third method takes advantage of the chemistry of mesionic compounds of the type described originally by R. Huisgen, et al., Ang. Chem. Int. Ed., 3: 136 (1964). In this procedure, detailed in Reaction Sequence 6, an ##STR23## N-alkyl-N-acylamino acid is treated with an acid anhydride and a substituted acetylenic compound to produce a pyrrole. For example, Reaction Sequence 6 shows how reaction of an alpha-halo ester, XXXII, with 2-(1-(2-aminoethyl))-1,3-dioxalane in triethylamine provides the N-alkyl-alpha-aminoester, XXXIII. The aminoester, XXXIII is acylated with an acid chloride and subsequently hydrolyzed in base to produce the N-acyl-N-alkyl aminoacid, XXXIV. Reaction of this latter compound with the desired substituted acetylenic compound, XXXV, produces the substituted pyrrole compounds, XXXVI. Acidic hydrolysis of XXXVI yields the aldehyde compounds, XXXVII, analogous to compounds XII of Reaction Sequence 1. Compounds of formula XXXVII are used in subsequent steps in a manner detailed in Reaction Sequence 1 to produce compounds of the present invention.
Preferred substituents for the substituted acetylenic compounds in this method of making compounds of the present invention include carboalkoxy groups, phenyl groups, alkanoyl groups, alkyl groups and cyano groups. The reaction between the disubstituted acetylene compound and the N-acyl-N-alkyl aminoacids, XXXIV, generally proceeds smoothly; for example, the dicarbomethoxy acetylene reacts smoothly at 25° C. However, when only one activating group is attached to the acetylene, the reaction mixture must generally be warmed to 70°-110° C. to obtain high yields of the pyrrole compounds.
A variety of other pyrroles can be derived from compounds of the general formula XXXVI when the groups R2 and R3 are carbomethoxy. Some of these transformations are detailed in Reaction Sequences 7 and 8. For example, as shown in Reaction Sequence 7, reduction of XXXVI with a reducing agent such as lithium aluminum hydride results in the bis(hydroxymethyl)pyrrole which can be subsequently further reduced to the dimethyl compound,
REACTION SEQUENCE 6 ##STR24## XXXVIII, by means of triethylsilane and trifluoroacetic acid employing the procedure of West, et al., J. Org. Chem., 38: 2675 (1973)).
Alternatively, as shown in Reaction Sequence 8, reaction of the compounds of formula XXXVI with a Grignard reagent or an alkyl-lithium reagent in the conventional manner followed by reduction and standard work-up affords the higher dialkylpyrroles, XXXIX.
Reaction of the diesters, XXXVI, or the corresponding diacids (obtained by conventional hydrolysis) with secondary amines provides the bis(dialkylamides), XL.
Alternatively, reaction of XXXVI with primary amines, followed by thermal cyclization in the conventional manner, provides the pyrrolosuccinimides, XLI, which can be reduced to XLII, if desired by reducing agents such as lithium aluminum hydride.
The bis(hydroxymethyl)pyrrole compounds derived from the lithium aluminum hydride reduction of XXXVI can be converted to their corresponding esters or carbamates by reaction with the desired acid anhydride or isocyanate, respectively. (See Anderson, et al., J. Med. Chem., 22: 977 (1979)).
The acids, XLIII, derived by convention hydrolysis of compounds of formula XXXVI can also be converted to the bis(amido)pyrroles, XLIV, which in turn can be dehydrated to produce the bis(nitrilo)pyrroles, XLV. Lastly, if desired, the bis(alkanoyl)pyrroles, XLVI, can be derived from the bis(nitrilo)pyrroles by reaction in the convention manner with the appropriate Grignard reagents.
The ring-opened dihydroxy-acids of structural formula II above are intermediates in the synthesis of the lactone compounds in accordance with the above-detailed reaction methods, or may be produced from the lactone compounds by conventional hydrolysis of the lactone compounds of formula I.
REACTION SEQUENCE 8 ##STR25##
In the ring-opened dihydroxy acid form, compounds of the present invention react to form salts with pharmaceutically acceptable metal and amine cations formed from organic and inorganic bases.
The term "pharmaceutically acceptable metal cation" contemplates positively charged metal ions derived from sodium, potassium, calcium, magnesium, aluminum, iron, zinc and the like.
The term "pharmaceutically acceptable amine cation" contemplates the positively charged ions derived from ammonia and organic nitrogenous bases strong enough to form such cations. Bases useful for the formation of pharmaceutically acceptable nontoxic base addition salts of compounds of the present invention form a class whose limits are readily understood by those skilled in the art.
The free acid form of the compound may be regenerated from the salt, if desired, by contacting the salt with a dilute aqueous solution of an acid such as hydrochloric acid.
The base addition salts may differ from the free acid form of compounds of this invention in such physical characteristics as melting point and solubility in polar solvents, but are considered equivalent to the free acid forms for purposes of this invention.
The compounds of this invention can exist in unsolvated as well as solvated forms. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol, and the like, are equivalent to the unsolvated forms for purposes of this invention.
The compounds of this invention are useful as hypocholesterolemic or hypolipidemic agents by virtue of their ability to inhibit the biosynthesis of cholesterol through inhibition of the enzyme 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase).
The ability of compounds of the present invention to inhibit the biosynthesis of cholesterol was measured by two methods. A first method (designated CSI screen) utilized the procedure described by R. E. Dugan et al., Archiv. Biochem. Biophys., (1972), 152, 21-27. In this method, the level of HMG-CoA enzyme activity in standard laboratory rats is increased by feeding the rats a chow diet containing 5% cholestyramine for four days, after which the rats are sacrificed.
The rat livers are homogenized, and the incorporation of cholesterol-14 C-acetate into nonsaponifiable lipid by the rat liver homogenate is measured. The micromolar concentration of compound required for 50% inhibition of sterol synthesis over a one-hour period is measured, and expressed as an IC50 value.
A second method (designated COR screen) employed the procedure detailed by T. Kita, et al., J. Clin. Invest., (1980), 66: 1094-1100. In this method, the amount of 14 C-HMG-CoA converted to 14 C-mevalonate in the presence of a purified enzyme preparation of HMG-CoA reductase was measured. The micromolar concentration of compound required for 50% inhibition of cholesterol synthesis was measured and recorded as an IC50 value.
The activity of several representative examples of compounds in accordance with the present invention appears in Table 1, and is compared with that of the prior art compound, compactin. In particular, compounds of the present invention where R2 and R3 are substituents other than hydrogen have activities comparable to that of the natural product, compactin.
                                  TABLE 1                                 
__________________________________________________________________________
 ##STR26##                                                                
                                        IC.sub.50                         
Com-                                    (Micromoles/Liter)                
pound                                                                     
    X      R.sub.1 R.sub.2                                                
                          R.sub.3                                         
                                 R.sub.4                                  
                                        CSI  COR                          
__________________________________________________________________________
1   CH.sub.2 CH.sub.2                                                     
           4-Fluorophenyl                                                 
                   H      H      CH(CH.sub.3).sub.2                       
                                        0.48 0.28                         
2   CH.sub.2 CH.sub.2                                                     
           4-Fluorophenyl                                                 
                   Cl     Cl     CH(CH.sub.3).sub.2                       
                                        0.16 0.024                        
3   CH.sub.2 CH.sub.2                                                     
           4-Fluorophenyl                                                 
                   Br     Br     CH(CH.sub.3).sub.2                       
                                        0.22 0.001                        
4   CH.sub.2 CH.sub.2                                                     
           4-Fluorophenyl                                                 
                   COOCH.sub.3                                            
                          COOCH.sub.3                                     
                                 CH(CH.sub.3).sub.2                       
                                        0.11 0.080                        
5   Compactin (prior art)                0.026                            
                                             0.028                        
__________________________________________________________________________
 *Adjusted for a standard IC.sub.50 value for compactin which was used as 
 an internal standard in the test.
For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersable granules, capsules, cachets, and suppositories.
A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material.
In powders, the carrier is a finely divided solid which is in a mixture with finely divided active compound. In tablets, the active compound is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
For preparing suppository preparations, a low-melting wax such as a mixture of fatty-acid glycerides and cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds and allowed to cool and solidify.
The powders and tablets preferably contain 5 to about 70% of the active ingredient. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and the like.
The term "preparation" is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier, which is thus in accordance with it. Similarly, cachets are included. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.
Liquid form preparations include solutions, suspensions, and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection. Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solution. Aqueous solutions for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired. Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water with viscous material, i.e., natural or synthetic gums, resins, methyl, cellulose, sodium carboxymethyl cellulose, and other well-known suspending agents.
Preferably, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, for example, packeted tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a capsule, cachet, or tablet itself or it can be the appropriate number of any of these packaged forms.
In therapeutic use as hypolipidemic or hypocholesterolemic agents, the compounds utilized in the pharmaceutical method of this invention are administered to the patient at dosage levels of from 40 mg to 600 mg per day. For a normal human adult of approximately 70 kg or body weight, this translates to a dosage of from about 0.5 mg/kg to about 8.0 mg/kg of body weight per day.
The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of optimum dosages for a particular situation is within the skill of the art.
The following examples illustrate particular methods for preparing compounds in accordance with this invention. These examples are illustrative and are not to be read as limiting the scope of the invention as it is defined by the appended claims.
EXAMPLE 1 Preparation of trans-6-[2-[2-(4-fluorophenyl)-5-(1-methylethyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one
Step A: Preparation of 1-(4-fluorophenyl)-5-methyl-1,4-hexanedione.
A mixture of 1-(4-fluorophenyl)-2-propene-1-one (43 g, 286.7 mmol) prepared in accordance with the method detailed in Org. Syn., Coll. Vol. IV, 305, was mixed with 31.2 ml (344 mmol) of isobutraldehyde, 28 ml (200 mmol) of triethylamine, and 14.5 g (57.7 mmol) of 2-(2-hydroxyethyl)-3-methyl-4-benzylthiazolium chloride and the mixture stirred under nitrogen at 70° C. for 12 hours.
After this time, the mixture was cooled to room temperature and the cooled mixture was partitioned between ether (500 ml) and water (100 ml). The aqueous layer was further extracted with 300 ml of ether, the ether solutions combined and washed successively with 200 ml of water, two 200-ml portions of 2M hydrochloric acid, and 100 ml of brine, and finally dried over anhydrous magnesium sulfate.
The ether was removed, and the residue was distilled (bp 115°-120° C., 0.2 mm Hg) to provide 36.7 g (165 mmol, 58% of 1-(4-fluorophenyl)-5-methyl-1,4-hexanedione which solidified upon standing.
Alternate Step A: Preparation of 1-(4-fluorophenyl)-5-methyl-1,4-hexanedione.
Isopropyl vinyl ketone (1.97 g, 20 mmol), prepared from isobutyryl chloride and vinyl trimethylsilane in accordance with the method detailed in Tet. Letters, (1979), 1995, was mixed with 4-fluorobenzaldehyde (2.4 g, 20 mmol), 2 ml (14 mmol) of triethylamine, and 1.0 g (4.0 mmol) of 2-(2-hydroxyethyl)-3-methyl-4-benzylthiazolium chloride. The mixture was stirred and heated under nitrogen for five hours. After cooling to room temperature, the mixture was partitioned between ether (200 ml) and water (50 ml). The water layer was extracted with 200 ml of ether and the ether solutions were combined. The combined ether solution was washed successively with 50 ml of water, two 50-ml portions of 2M hydrochloric acid, and 50 ml of brine. The ether solution was dried over anhydrous magnesium sulfate. After removal of the ether, the remaining liquid was flash chromatographed on silica gel eluting with 20:1 (volume/volume) hexane-ethyl acetate. This procedure afforded 2.59 g of pure 1-(4-fluorophenyl)-5-methyl-1,4-hexanedione, mp 47°-49° C.
Step B: Preparation of 2-[2-[2-(4-fluorophenyl)-5-(1-methylethyl)-5-methyl-1H-pyrrol-1-yl]]-1-cyanoethane.
A solution of 1-(4-fluorophenyl)-5-methyl-1,4-hexanedione (36.5 g, 164 mmol), 3-aminopripionitrile.1/2 fumarate (23.1 g, 180.4 mmol), and p-toluenesulfonic acid (0.1 g) in 250 ml of glacial acetic acid was stirred and heated under reflux under nitrogen for six hours. After cooling to room temperature, the mixture was poured into 500 ml of ice-water and the water suspension which resulted was extracted with two 600-ml portions of ether. The combined ether extract was washed successively with rwo 200-ml portions of water, three 200-ml portions of sodium bicarbonate, and a 200-ml portion of brine and then dried over anhydrous magnesium sulfate.
The ether was removed, and the liquid which remained was flash chromatographed on silica gel, eluting with 10:1 (volume/volume) hexane-ethyl acetate to yield 34.8 g of oily 2-[2-[2-(4-fluorophenyl)-5-(1-methylethyl)-1H-pyrrol-1-yl]]-1-cyanoethane which solidified upon standing.
Recrystallization from isopropyl ether provided analytical material of melting point 78°-80° C.
Anal. Calcd. for C16 H17 FN2 : C, 74.97%; H, 6.69%; N, 10.93%. Found: C, 75.18%; H, 6.64%; N, 10.93%.
Step C: Preparation of 3-[2-[2-(4-fluorophenyl)-5-(1-methylethyl)-1H-pyrrol-1-yl]]-1-propanal.
To a stirred solution of 2-[2-[2-(4-fluorophenyl)-5-(1-methylethyl)-1H-pyrrol-1-yl]]-1-cyanoethane (34.8 g, 135.8 mmol) in 300 ml of dichloromethane at ambient temperature under nitrogen was added dropwise over 30 minutes 156.2 ml of a 1.0M solution of diisobutyl-aluminum ("DiBAL") in dichloromethane. The resulting mixture was stirred for three hours, after which another 20 ml of 1.0M DiBAL solution was added. The mixture was stirred overnight at room temperature, after which the excess hydrode was destroyed by cautious addition of methanol. When gas evolution had ceased, the solution was carefully poured into 500 ml of vigorously stirred ice-cold 2M hydrochloric acid.
The emulsion which resulted was extracted with two 500-ml portions of ether and the combined ether extracts were washed successively with 100 ml of water, two 100-ml portions of sodium bicarbonate solution, and 100 ml of brine, and then dried over anhydrous magnesium sulfate. The ether was removed and the residue was flash chromatographed over silica gel, eluting with 10:1 (volume/volume) hexane-ethyl acetate, yielding pure 3-[2-[2-(4-fluorophenyl)-5-(1-methylethyl)-1H-pyrrol-1-yl]]-1-propanal.
Step D: Preparation of methyl 7-[2-[2-(4-fluorophenyl)-5-(1-methylethyl)-1H-pyrrol-1-yl]]-5-hydroxy-3-oxo-heptanoate.
To a stirred suspension of 2.17 g (90.6 mmol) of hexane-washed sodium hydride in 200 ml of anhydrous tetrahydrofuran, cooled to 0° C. under nitrogen, was added dropwise over a period of 30 minutes a solution of 8.9 ml (82.4 mmol) of methyl acetoacetate in 150 ml of anhydrous tetrahydrofuran. When gas evolution had ceased, 39.3 ml of a 2.1M solution of n-butyl lithium in hexane was added dropwise. The resulting solution was stirred for 30 minutes after which a solution of 19.4 g (74.9 mmol) of 3-[2-[2-(4-fluorophenyl)-5-(1-methylethyl)-1H-pyrrol-1-yl]]-1-propanol in 150 ml of anhydrous tetrahydrofuran was added dropwise over a period of 30 minutes. The solution was stirred for an additional hour before quenching the reaction by the addition of 100 ml of saturated aqueous ammonium chloride solution, followed by 100 ml of 2M hydrochloric acid solution.
The resulting mixture was partitioned between ether (500 ml) and water (100 ml). The water layer was separated and extracted with 300 ml of ether. The ether extracts were combined and washed with 50 ml of brine and then dried over anhydrous magnesium sulfate. The ether was removed and the residue was flash chromatographed on silica gel, eluting with 5:1 (volume/volume) hexane-ethyl acetate to yield 19.9 g (64%) of methyl 7-[2-[2-(4-fluorophenyl)--5-(1-methylethyl)-1H-pyrrol-1-yl]]-5-hydroxy-3-oxo-heptanoate.
Step E: Preparation of trans-6-[2-[2-(4-fluorophenyl)-5-(1-methylethyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
Thirty ml of air (syringe) were bubbled through a solution of 58 ml of a 1M solution of tributylborane in tetrahydrofuran containing 19.9 g (53 mmol) of methyl 7-[2-[2-(4-fluorophenyl)--5-(1-methylethyl)-1H-pyrrol-1-yl]]-5-hydroxy-3-oxo-heptanoate under nitrogen at room temperature. The solution was then stirred for 18 hours at room temperature and then cooled to -78° C. Sodium borohydride (2.27 g, 60 mmol) was then added in one portion. The mixture was stirred for 60 minutes at -78° C. and for 90 minutes at 0° C. A mixture of 10 ml water and 10 ml of methanol was carefully added (gas evolution). Sixty ml of 3M sodium hydroxide solution and 30 ml of 30% H2 O2 solution were simultaneously added to the mixture from separation dropping funnels. The vigorously stirred mixture was held at 0° C. for 60 minutes and then at room temperature for two hours.
The mixture was then partitioned between 300 ml of water and 300 ml of ether. The ether layer was extracted with 50 ml of 10% sodium hydroxide solution and the water layers were combined, acidified with concentrated hydrochloric acid, and extracted with two 500-ml portions of ethyl acetate. The ethyl acetate extracts were combined, washed twice with brine, and dried over anhydrous magnesium sulfate. Removal of the ethyl acetate yielded 12.5 g of an oily acid which was dissolved in 500 ml of toluene and heated to azeotropically remove water. After cooling the solution to room temperature and removing the toluene, the residue was flash chromatographed on silica gel, eluting with 2:1 hexane-ethyl acetate (volume/volume) to yield 11 g of a colorless solid. Recrystallization from diisopropyl ether yielded 9.5 g (52%) of trans-6-[2-[2-(4-fluorophenyl-5-(1-methylethyl)-1H-pyrrol-1-yl]tetrahydro-4-hydroxy-2H-pyran-2-one,
mp 104°-105° C.
Anal. Calcd. for C20 H24 FNO3 : C, 70.42; H, 7.00; N, 4.06; Found: C, 70.26; H, 7.33; N, 3.99.
EXAMPLE 2 Preparation of trans-6-[2-[2-(4-fluorophenyl)-5-methyl-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one
The procedure of Example 1 was employed with the substitution of equimolar amounts of 4-fluorobenzaldehyde and 3-butene-2-one for the 1-(4-fluorophenyl)-2-propene-1-one and isobutyraldehyde in Step A of Example 1. Thereafter, the procedure of Steps B-E were followed to produce trans-6-[2-[2-(4-fluorophenyl)-5-methyl-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
Anal. Calcd. for C18 H20 FNO3 : C, 68.12; H, 6.35; N, 4.41; Found: C, 68.39; H, 6.18; N, 4.25.
EXAMPLE 3 Preparation of trans-6-[2-[2-cyclopropyl-5-(4-fluorophenyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one
The procedure of Example 1 was employed with the substitution of equimolar amounts of 4-fluorobenzaldehyde and 1-cyclopropyl-2-propene-1-one for the 1-(4-fluorophenyl)-2-propene-1-one and isobutyraldehyde in Step A of Example 1. Thereafter, the procedure of Steps B-E were followed to produce trans-6-[2-[2-cyclopropyl-5-(4-fluorophenyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
Anal. Calcd. for C20 H22 FNO3 : C, 69.69; H, 6.46; N, 4.08; Found: C, 70.02; H, 6.54; N, 4.01.
EXAMPLE 4 Preparation of trans-6-[2-[2-(1,1-dimethylethyl)-5-(4-fluorophenyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one
The procedure of Example 1 was employed with the substitution of equimolar amounts of 4-fluorobenzaldehyde and t-butyl vinyl ketone for the 1-(4-fluorophenyl)-2-propene-1-one and isobutyraldehyde in Step A of Example 1. Thereafter, the procedure of Steps B-E were followed to produce trans-6-[2-[2-(1,1-dimethylethyl)-5-(4-fluorophenyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one, mp 177°-178° C.
Anal. Calcd. for C21 H26 FNO3 : C, 70.17; H, 7.29; N, 3.90; Found: C, 70.22; H, 7.50; N, 3.80.
Example 5 Preparation of trans-6-[2-(5-phenyl-2-methyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one
The procedure of Example 1 was employed with the substitution of equimolar amounts of benzaldehyde and 3-butene-2-one for the 1-(4-fluorophenyl)-2-propene-1-one and isobutyraldehyde in Step A of Example 1. Thereafter, the procedure of Steps B-E were followed to produce trans-6-[2-(5-phenyl-2-methyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran2-one, mp 95°-96° C.
Anal. Calcd. for C19 H23 NO4 : C, 69.28; H, 7.04; N, 4.25; Found: C, 68.93; H, 7.00; N, 4.10.
EXAMPLE 6 Preparation of trans-tetrahydro-4-hydroxy-6-[2-[2-(2-methoxyphenyl)-5-methyl-1H-pyrrol-1-yl]ethyl]-2H-pyran-2-one
The procedure of Example 1 was employed with the substitution of equimolar amounts of 2-methoxybenzaldehyde and methyl vinyl ketone for the 4-(fluorobenzaldehyde and isopropyl vinyl ketone in Alternate Step A of Example 1. Thereafter, the procedure of Steps B-E were followed to produce trans-tetrahydro-4-hydroxy-6-[2-[2-(2-methoxyphenyl)-5-methyl-1H-pyrrol-1-yl]ethyl]-2H-pyran-2-one, mp 112.5°-113.5° C.
Anal. Calcd. for C19 dH23 NO4 : C, 69.28; H, 7.04; N, 4.25; Found: C, 69.04; H, 7.22; N, 4.17.
EXAMPLE 17 Preparation of trans-tetrahydro-4-hydroxy-6-[2-[2-(4-methoxyphenyl)-5-methyl-1H-pyrrol-1-yl]ethyl]-2H-pyran-2-one
The procedure of Example 1 was employed with the substitution of equimolar amounts of 4-methoxybenzaldehyde and 3-butene-2-one for the 1-(4-fluorophenyl)-2-propene-1-one and isobutyraldehyde in Step A of Example 1. Therafter, the procedure of Steps B-E were followed to produce trans-tetrahydro-4-hydroxy-6-[2-[2-(4-methoxyphenyl)-5-methyl-1H-pyrrol-1-yl]ethyl]-2H-pyran-2-one, mp 95°-95° C.
Anal. Calcd. for C19 H23 NO4 :C, 69.28; H, 7.04; N, 4.25; Found: C, 68.93; H, 7.00; N, 4.10.
EXAMPLE 8 Preparation of trans-6-[2-(2-cyclohexyl-5-methyl-1H-pyrrol-1-yl)ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one
The procedure of Example 1 was employed with the substitution of equimolar amounts of cyclohexanecarboxaldehyde and 3-butene-2-one for the 1-(4-fluorophenyl)-2-propene-1-one and isobutyraldehye in Step A of Example 1. Thereafter, the procedure of Steps B-E were followed to produce trans-6-[2-(2-cyclohexyl-5-methyl-1H-pyrrol-1-yl)ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one, mp 129°-130° C.
Anal. Calcd. for C18 H27 NO3 : C, 70.79; H, 8.91; N, 4.59; Found: C, 71.11; H, 8.71; N, 4.47.
EXAMPLE 9 Preparation of trans-tetrahydro-4-hydroxy-6-[2-[2-methyl-5-[3-(trifluoromethyl)phenyl]-1H-pyrrol-1-yl]ethyl]-2H-pyran-2-one
The procedure of Example 1 was employed with the substitution of equimolar amounts of 3-(trifluoromethyl)benzaldehyde and 3-butene-2-one for the 1-(4-fluorophenyl)-2-propene-1-one ad isobutyraldehyde in Step A of Example 1. Thereafter, the procedure of Steps B-E were followed to produce trans-tetrahydro-4-hydroxy-6-[2-[2-methyl-5-[3-(trifluoromethyl)phenyl]-1H-pyrrol-1yl]ethyl]-2H-pyran-2-one.
Anal. Calcd. for C19 H20 F3 NO3 : C, 62.12; H, 5.49; N, 3.81; Found: C, 62.22; H, 5.61; N, 3.73.
EXAMPLE 10 Preparation of trans-6-[2-[2-([1,1'-biphenyl]-4-yl)-5-methyl-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one
The procedure of Example 1 was employed with the substitution of equimolar amounts of 4-phenylbenzaldehyde and 3-butene-2-one for the 1-(4-fluorophenyl)-2-propane-1-one and isobutyraldehyde in Step A of Example 1. Thereafter, the procedure of Steps B-E were followed to produce trans-6-[2-[2-([1,1'-biphenyl]-4-yl)-5-methyl-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one, mp 104°-107° C.
Anal. Calcd. for C24 H25 NO3 : C, 76.77; H, 6.71; N, 3.73; Found: C, 76.66; H, 6.66; N, 3.71.
EXAMPLE 11 Preparation of trans-tetrahydro-4-hydroxy-6-[2-[2-methyl-5-(1-naphthalenyl)-1H-pyrrol-1-yl]-2H-pyran-2-one
The procedure of Example 1 was employed with the substitution of equimolar of 1-naphthaldehyde and 3-butene-2-one for the 1-(4-fluorophenyl)-2-propene-1-one and isobutyraldehyde in Step A of Example 1. Thereafter, the procedure of Steps B-E were followed to produce trans-tetrahydro-4-hydroxy-6-[2-[2-methyl-5-(1-naphthalenyl)-1H-pyrrol-1-yl]ethyl]-2H-pyran-2-one, mp 137°-138° C.
EXAMPLE 12 Preparation of trans-tetrahydro-4-hydroxy-6-[2-[2-methyl-5-(2-naphthalenyl)-1H-pyrrol-1-yl]ethyl]-2H-pyran-2-one
The procedure of Example 1 was employed with the substitution of equimolar amounts of 2-naphthaldehyde and 3-butene-2-one for the 1-(4-fluorophenyl)-2-propene-1-one and isobutyraldehyde in Step A of Example 1. Thereafter, the procedure of Steps B-E were followed to produce trans-tetrahydro-4-hydroxy-6-[2-[2-methyl-5-(2-naphthalenyl)-1H-pyrrol-1-yl]ethyl]-2H-pyran-2-one, mp 45°-50° C.
Anal. Calcd. for C22 H23 NO3 : C, 75.62; H, 6.63; N, 4.00; Found: C, 75.12; H, 6.88; N, 3.97.
EXAMPLE 13 Preparation of trans-6-[2-(bicyclo[2.2.1]hept-5-en-2-yl-5-methyl-1H-pyrrol-1-yl)ethyl]-tetrahydro-4-hydroxy-2H-pyran-2-one
The procedure of Example 1 was employed with the substitution of equimolar amounts of bicyclo [2.2.1]hept-5-ene-2-carboxyaldehyde (mixture of diastereomers) and 3-butene-2-one for the 1-(4-fluorophenyl)-2-propene-1-one and isobutyraldehyde in Step A of Example 1. Therafter, the procedure of Steps B-E were followed to produce trans-6-[2-(2-bicyclo[2.2.1]hept-5-en-2-yl-5-methyl-1H-pyrrol-1-yl)ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one as a 1:1 mixture of the ando- and exoisomers at the norbornene ring, mp 125°-126° C.
Anal. Calcd. for C19 H25 NO3 : C, 72.35; H, 7.99; N, 4.44; Found: C, 72.11; H, 8.02; N, 4.32.
EXAMPLE 14 Preparation of trans-6-[2-[2-(diphenylmethyl)-5-methyl-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one
The procedure of Example 1 was employed with the substitution of equimolar amounts of diphenylacetaldehyde and 3-butene-2-one for the 1-(4-fluorophenyl)-2-propene-1-one and isobutyraldehyde in Step A of Example 1. Thereafter, the procedure of Steps B-E were followed to produce trans-6-[2-[2-diphenylmethyl)-5-methyl-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one, mp 129°-132° C.
Anal. Calcd. for C25 H27 NO3 : C, 77.07; H, 6.99; N, 3.60; Found: C, 76.85; H, 7.14; N, 3.45.
EXAMPLE 15 Preparation of trans-6-[2-[2-(4-fluorophenyl)-5-(1-methylethyl)-1H-pyrrol-1-yl]propyl]tetrahydro-4-hydroxy-2H-pyran-2-one
The procedure of Example 1 was employed with the substitution in Step B of 2-aminopropanol in place of the ethanolamine. Therafter, the procedure of Steps C-E were followed to produce trans-6-[2-[2-(4-fluorophenyl)-5-(1-methylethyl)-1H-pyrrol-1-yl]propyl]tetrahydro-4-hydroxy-2H-pyran-2-one, mp 167°-169° C.
Anal. Calcd. for C21 H26 FNO3 : C, 70.17; H, 7.29; N, 3.90; Found: C, 70.06; H, 7.36; H, 7.36; N, 3.82.
EXAMPLE 16 Preparation of trans-tetrahydro-4-hydroxy-6-[2-[2-(2-methoxyphenyl)-5-(1-methylethyl)-1H-pyrrol-1-yl-ethyl]-2H-pyran-2-one
The procedure of Example 1 was employed with the substitution of equimolar amounts of 2-methoxybenzaldehyde and 3-butene-2-one for the 1-(4-fluorophenyl)-2-propene-1-one and isobutyraldehyde in Step A of Example 1. Thereafter, the procedure of Steps B-E were followed to produce trans-tetrahydro-4-hydroxy-6-2-[2-(2-methoxyphenyl)-5-(1-methylethyl)-1H-pyrrol-1-yl-ethyl]-2H-pyran-2-one.
Anal. Calcd. for C21 H27 NO3 : C, 70.56; H, 7.61; N, 3.92; Found: C, 70.43; H, 7.66; N, 3.73.
EXAMPLE 17 Method 1
Step A: Preparation of 6-[2-[2-(4-fluorophenyl)-5(1-methylethyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-tert-butyl dimethylsilyloxy-,trans-2H-pyran-2-one.
To a solution of 6-[2-[2-(4-fluorophenyl)-5-(1-methylethyl)-1H-pyrrol-1-yl]ethyl]-tetrahydro-4-hydroxy-trans-2H-pyran-2-one (0.52 g, 1.5 mmoles) and tert-butyldimethylchloro silane (0.27 g, 1.8 mmoles) in 5 ml of dry DMF was added imidazole (0.31 g, 4.5 mmoles) in one portion. The solution was stirred overnight at room temperature before partitioning between hexane (100 ml) and water (50 ml). The aqueous layer was extracted with two 50 ml portions of hexane. The combined hexane extracts were washed with H2 O (2×25 ml), brine (25 ml), and dried (MgSo4) Filtration through silica gel and concentration provided 0.7 g (100%) of the title compound. 80 MHz NMR (CDCl3) δ 0.10 (S, 6H), 0.90 (S, 9H), 1.30 (d, J=Hz 6H), 1.4-1.8 (m, 4H), 2.48 (m, 2H), 2.95 (m, 1H), 3.9-4.3 (m, 3H), 5.85 (d, J=2 Hz 1H), 6.02 (d, J=2 Hz, 1H), 6.8-7.3 (m, 4H).
Step B: Preparation of 6-[2-[2-(4-fluorophenyl)-3,4-dichloro-5-(1-methylethyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-trans-2H-pyran-2-one.
N-Chlorosuccinimide (6.48 mmoles, 0.87 g) was added in one portion to a stirred solution of 6-[2-[2-(4-fluorophenyl)-5-(1-methylethyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-tert-butyldimethylsilyloxy-trans-2H-pyran-2-one (1.49 g, 3.24 mmoles) in dry DMF (10 ml) cooled to 0° C. under dry nitrogen. The solution was stirred for one hour at 0° C. then warmed to room temperature for three hours. It was then diluted with water (50 ml) and extracted with ether (2×1000 ml). The ether extracts were diluted with 100 ml of hexane and washed with water (50 ml), 10% aq. NaHCO3 (50 ml), 10% aq. NaHSO3 (50 ml), brine (50 ml), and dried (MgSO4). The crude product which remained after filtration and concentration was dissolved in tetrahydrofuran (15 ml) and treated with glacial acetic acid (0.75 ml, 13 mmoles) and tetrabutyl ammonium fluoride (9.72 ml of 1M THF solution). The solution was stirred for five hours, diluted with ethyl acetate (100 ml) and washed with saturated aq. NaHCO3 (2×50 ml), brine (25 ml), and dried (MgSO4). The residue which remained after filtration and concentration was flash chromatographed on silica gel eluting with 2:1 hexane-ethyl acetate. This provided 0.50 g (35%) of pure lactone. Recrystallization from ether-hexane provided colorless crystals mp 129°-131° C.
Anal. Calcd. for C20 H22 FCL2 NO3 : C, 57.98; H, 5.35; N, 3.38; Found: C, 58.24; H, 5.24; N, 3.39.
IR (KBr) v 3550, 2990, 1711, 1518, 12225, 1160, 1055, 851, 816 cm-1 200 MHz NMR (CDCL3) δ 1.44 (d, J=7 Hz, 6H), 1.8 (m, 4H), 2.12 (d, J=3 Hz, 1H, --OH), 2.55 (m, 2H), 3.10 (M, 1H), 4.0 (M, 2H), 4.30 (M, 1H), 4.45 (M, 1H), 7.0-7.4 (M, 4H).
Method 2
Step A: Preparation of 2-(4-fluorophenyl)-5-(1-methylethyl)-3,4-dichloro-1H-pyrrole-1-propanenitrile.
N-Chlorosuccininide (practical, 105 g, 786.5 mmoles) was added in one portion to a stirred solution of 2-(4-fluorophenyl)-5-(1-methylethyl)-1H-pyrrole-1-propanenitrile (84 g, 327.7 mmoles) in 500 ml of dry dimethylformamide cooled to 0° C. under nitrogen. After stirring for 60 minutes at 0° C. and 90 minutes at 25° C., a further 8 g (60 mmoles) of N-chlorosuccininide were added. The solution was stirred a further 60 minutes before pouring into ether (3 liters) and washing with H2 O (3×500 ml), 10% aq. NaHSO3 (300 ml), H2 O (300 ml), brine, and dried (MgSO4). Flash chromatography on silica gel eluting with 10:1 hexane-ethyl acetate provided an oil which solidfied on standing. Recrystallization from isopropyl ether-hexane provided 96 g of colorless crystals mp 80°-82° C.
Anal. Calcd. for C16 H15 CL2 FN2 : C, 59.09; H, 4.65; N, 8.61; Found: C, 59.01; H, 4.56; N, 8.59.
IR (KBr) 2933, 2249, 1520, 1490, 1344, 1315, 1218, 848, 524 cm-1. 100 MHz NMR (CDCl3) δ 1.42 (d, J=7 Hz, 6H), 2.33 (t, J=7 Hz, 2H), 3.0 (sptet, J=7 Hz, 1H), 4.05 (t, J=7 Hz, 2H), 70-74 (M, 4H).
Employing the product of this step in the process described above in Step C of Example 1, provided 6-[2-[2-(4-fluorophenyl)-3,4-dichloro-5-(1-methylethyl)-1H-pyrrol-1-yl]-ethyl]tetrahydro-4-hydroxy-trans-2H-pyran-2-one.
EXAMPLE 18 Preparation of 6-[2-[2-(4-fluorophenyl)-3,4 dibromo-5-(1-methylethyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-trans-2H-pyran-2-one
Substitution of N-Bromosuccinimide for N-Chlorosuccinimide in Step B of Method 1, Example 17 provided a corresponding amount of the title compound mp 143° C.
Anal. Calcd. for C20 H22 FBr2 NO3 : C, 47.74; H, 4.41; N, 2.78; Br, 31.76; F, 3.77. Found: C, 47.52; H, 4.34; N, 2.84. Br, 31.75; F, 3.72.
IR (KBr) 3350, 2966, 1711, 1510, 1484, 1225, 1072, 847, 820 cm-1. 200 MHz NMR (CDCl3) δ 1.40 (d, J=7 Hz, 6H), 1.5-1.8 (m, 41t), 1.94 (brs, 1H, --OH), 2.58 (m, 2H), 3.13 (m, 1H), 4.0 (m, 2H), 4.31 (m, 1H), 4.47 (m, 1H), 7.0-7.3 (m, 4H).
EXAMPLE 19
Step A: Preparation of ethyl-2(1-(1-oxo-2,2,2-trifluoroethyl))-4-oxo-4-(4-fluorophenyl)-butyrate
A solution of ethyl 1,1,1-trifluoroacetoacetate (14.6 ml, 0.1 mole) in dry DMF (100 ml) was added dropwise to a 0° C. suspension of hexane washed sodium hydride (0.106 mole) in 50 ml of dry DMF under nitrogen. When gas evolution was complete, a solution of α-bromo-4'-fluoroacetophenone (0.1 mole,) prepared as in J. Org. Chem. 29, 3459 (1964)) in 100 ml of dry DMF was added dropwise over 30 minutes. The mixture was allowed to warm slowly to 25° C. overnight. It was then quenched by addition of 6N HCl, poured into H2 O (1 liter) and extracted with ether (2×500 ml). The combined ether extracts were washed with H2 O (2×100 ml), brine (100 ml), and dried (MgSO4). Flash chromatography on silica gel eluting with 5:1 hexane-ethylacetate provided 7 g of the title compound. IR (film) 3380, 1768, 1744, 1688, 1601, 1511, 1413, 1293, 1263, 1238, 1212, 1160, 1100, 1004, 841 cm-1. 200 MHz NMR (CDCl3) δ 1.29 (t, J=7 Hz, 3H), 3.75 (m, 2H), 4.26 (q, J=7 Hz, 2H), 4.55 (dd, J=4.7, 9.6 Hz, 1H), 7.21 (m, 2H), 8.02 (m, 2H)
Step B: Preparation of 2-(4-fluorophenyl)-5-trifluoromethyl-1H-pyrrole-1-propanenitrile.
A solution of ethyl-2-(1-(1-oxo-2,2,2-trifluoroethyl))-4-oxo-4-(4-fluorophenyl)-butyrate (5 g, 15.6 mmoles) in 110 ml of 5:5:1 acetic acid-water-conc. sulfuric acid was stirred and heated at reflux for four hours. The cooled solution was carefully poured into 400 ml of saturated aq. bicarbonate which was then extracted with ether (2×300 ml). The combined ether extracts were washed with saturated aq. bicarbonate (2×50 ml), brine (50 ml), and dried (MgSO4). The crude diketone which remained after filtration and concentration (3 g) was dissolved in 20 ml of glacal acetic acid and 2 g (18 mmoles) of 3-aminopropanenitrile-1/2-fumarate were added. The solution was stirred and heated at reflux for five hours. The cooled solution was poured into 200 ml of saturated aq. bicarbonate and extracted with ether (2×200 ml). The combined ether extracts were washed with H2 O (2×50 ml), brine (50 ml), and dried (MgSO4). Flash chromatography of the residue which remained after filtration and concentration provided 1.2 g (27%) of the title compound. IR (CDCl3) 2258, 1611, 1570, 1478, 1337, 1172, 1106, 1064, 844 cm-1. 200 MHz NMR (CDCL3) δ 2.51 (t, J=7.3 Hz, 2H), 4.30 (t, J=7 Hz, 2H), 6.16 (d, J=3.8 Hz, 1H), 6.67 (d, J=3.8 Hz, 1H), 7.1-7.5 (m, 4H). Mass spectrum M/e 282, 263, 242, 229, 173.
Preparation of 6-[2-[2-trifluoromethyl]-5-(4-fluorophenyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-trans-2H-pyran-2-one.
Substitution of 2-(4-fluorophenyl)-5-trifluoromethyl-1H-pyrrole-1-propanenitrile for 2-(4-fluorophenyl)-3,4-dichloro-5-(1-methylethyl)-1H,-pyrrole-1-propanenitrile in Step C of Example 1 and following the procedures of Step C, D, and E resulted in a corresponding amount of the title compound as an oil.
Anal. Calcd. for C18 H17 F4 NO3 : C, 58.22; H, 4.61; N, 3.77. Found: C, 58.88; H, 5.07; N, 4.03.
IR (film) 3440, 2927, 1728, 156, 1477, 1342, 1266, 1230, 1160, 1101, 1060, 843, 782 cm-1. 200 MHz NMR (CDCl3) δ 1.3-2.1 (m, 4H), 2.34 (brs, 1H, --OH), 2.55 (m, 2H), 3.9-4.3 (m, 3H), 4.52 (m, 1H), 6.11 (d, J=3.8 Hz, 1H), 6.61 (dd, J=0.8, 3.8 Hz, 1H), 7.0-7.4 (m, 4H).
EXAMPLE 20 Preparation of (±)-N-(4-fluorobenzoyl)-N-[2-(2-ethyl)-1,3-dioxolanyl]valine
A solution of the methyl-2-bromo-3-methyl butyrate (4.6 g, 23.6 mmoles), 2-(1-(2-aminoethyl))-1,3-dioxolane (2.93 g, 25 mmoles) and triethylamine (3.5 ml, 25 mmoles) was stirred and heated in 25 ml of refluxing acetonitrile for 20 hours. The cooled solution was poured into ether (500 ml) and extracted 2M HCl (2×50 ml). The aqueous layer was made alkaline with 25% aq. NaOH and extracted with ethyl acetate (2×100 ml). The combined ethyl acetate extracts were washed with brine and dried (MgSO4). Filtration and concentration provided 3 g of the title compound as liquid. 90 MHz NMR (CDCl3) δ 0.9.3 (d, J=7 Hz, 6H), 1.70 (brs, 1H, --NH), 1.86 (m, 2H), 2.60 (m, 3H) 2.94 (d, J=6 Hz, 1H), 3.68 (s, 3H), 3.85 (m, 4H), 4.89 (t, J=4 Hz, 1H).
Preparation of ±-Methyl-N-(4-fluorobenzoyl)-N-[2-(2-ethyl)-1,3 dioxolanyl]valine.
To a stirred solution of Methyl-N-[2-(2-ethyl)-1,3-dioxolanyl]valine (3 g, 13 mmoles) and triethylamine (3.6 ml, 26 mmoles) in 20 ml of dichloromethane (CH2 CL2) cooled to 0° C. was added a solution of 4-fluorobenzoyl chloride (1.65 ml, 14 mmoles) in 10 ml of (CH2 CL2). The solution was stirred 60 minutes at 0° C. and 60 minutes at room temperature. It was then poured into ether and washed with water, saturated aq. bicarbonate, brine, and dried (MgSO4). Flash chromatography on silica gel eluting with 1:1 hexane-ethyl acetate provided 3 g of the title compound. 90 MHz NMR (CDCl3) δ 0.90, (brd, J=7 Hz, 6H), 1.8-2.5 (m, 3H), 3.45 (br, dd, J=6, 8 Hz, 1H), 3.72 (s, 3H), 3.80 (m, 6H), 4.80 (m, 1H), 6.9-7.5 (m, 4H).
Preparation of ±-N-(4-fluorobenzoyl)-N-[2-(2-ethyl)-1,3-dioxolyanyl]valine.
A solution of the methyl ester prepared above (1 g, 2.83 mmoles) and NaOH (0.4 g, 10 mmoles) in 10 ml of 4:1 CH3 OH--H--2 O was stirred and heated at reflux for three hours. The cooled solution was diluted with water and extracted with ether. The aqueous layer was acidified with 6M HCl and extracted with ethyl acetate. (2×). The combined ethyl acetate extracts were washed with brine and dried (MgSO4). Filtration and concentration provided 0.96 g (2.8 mmoles) of acid. 90M Hz NMR (CDCl3) δ 0.85 (m, 6H), 1.8 (m, 2H), 2.5 (m, 1H) 3.3-3.9 (m, 7H), 4.6 (m, 1H) 6.8-7.4 (m, 4H).
Preparation of dimethyl--[2-(2-ethyl)-1,3-dioxolanyl]dioxolanyl]-2-(4-fluorophenyl)-5-(1-methyl-ethyl)-1H-pyrrole-3,4-dicarboxylate
Dimethyl acetylene dicarboxylate (1.3 ml, 10.6 mmoles) was added to a 25° C. solution of (±)-N-(4-fluorobenzoyl)-N-[2-(2-ethyl)-1,3-dioxolanyl]valine (1.8 g, 5.28 mmoles) dissolved in 10 ml of acetic anhydride. The evolution of carbon dioxide began immediately. The solution was stirred a further two hours, concentrated to remove excess acetylene and solvent, then filtered through silica gel. This provided 2 g of pyrrole as a solid which was recrystallized from isopropyl ether-hexane
mp 143°-146° C.
Anal. Calcd. for C22 H26 FNO6 C, 62.55; H, 6.20; N, 3.31. Found: C, 62.84; H, 6.23; N, 3.30.
IR (KBr) 1719, 1449, 1241, 1209, 1178, 945 cm-1. 200 MHz NMR (CDCl3) δ 1.35 (d, J=7 Hz, 6H), 1.80 (m, 2H), 3.18 (Septet, J=7 Hz, 1H), 3.56 (s, 3H), 1H), 3.7-4.0 (m, 6H), 3.83 (S, 3H), 4.64 (t, J=4 Hz, 1H), 7-7.3 (m, 4H).
Preparation of Dimethyl-1-(1-(3-oxopropyl))-2-(4-fluorophenyl)-5-(1-methylethyl)-1H-pyrrole-3.4-dicarboxylate
A solution of dimethyl-1-[2-(2-ethyl)-1,3-dioxolanyl)-2-(4-fluorophenyl)-5-(1-methylethyl)-1H-pryrrole-3,4-dicarboxylate (0.5 g, 1.18 mmoles) and p-toluenesulfonic acid (0.23 g, 1.2 mmoles) in 12 ml of 5:1 acetone-water was stirred and heated at reflux for 48 hours. The cooled solution was concentrated, diluted with ether (200 ml), washed with saturated aq. bicarbonate (2×50 ml), brine (50 ml), and dried (MgSO4). Flash chromatography on silica gel eluting with 4:1 hexane-ethyl acetate provided 0.4 g of pure aldehyde.
90 MHz NMR (CDCl3) δ 1.35 (d, J=7 Hz, 6H), 2.61 (t, J=7 Hz, 2H), 3.18 (septet, J=7 Hz, 1H), 3.53 (s, 3H), 3.81 (s, 3H), 4.03 (t, J=7 Hz, 2H), 6.9-7.3 (M, 4H), 9.45 (s, 1H).
Preparation of Dimethyl-2-(4-Fluorophenyl)-5-(1-methylethyl)-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3,4-dicarboxylate.
Substituion of dimethyl-1(1-(3-oxopropyl))-2-(4-fluorophenyl)-5-(1-methylethyl)-1H-pyrrole-3,4-dicarboxylate for 2-(4-fluorophenyl)-5-(1-methylethyl)-1H-pyrrole-1-propanol in Step C of Example 1 and following the procedures of Steps C, D, and E provided a corresponding amount of the title compound mp 167°-170° C.
Anal. Calcd. for C24 H28 FNO7 C, 62.47; H, 6.12; N, 3.04. Found: C, 62.32; H, 5.87; N, 2.99.
IR (KBr) 2450, 2980, 1719, 1499, 1225, 1174, 1074, 811 cm-1. 200 MHz NMR (CDCl3) δ 1.34 (d, J=7 Hz, 6H), 1.57 (m, 4H), 2.40 (d, J=3 Hz, 1H), 2.56 (m, 2H), 3.16 (septet, J=7 Hz, 1H), 3.55 (s, 3H), 3.83 (s, 3H), 4.0 (m, 2H), 4.26 (m, 1H), 4.44 (m, 1H), 4.44 (m, 1H), 7.1-7.3 (m, 4H).

Claims (19)

We claim:
1. A compound having the structural formula ##STR27## wherein X is
--CH2 --,
--CH2 CH2 --, or
--CH(CH3)CH2 --;
R1 is
1-naphthyl,
2-naphthyl,
cyclohexyl,
norbornenyl,
phenyl,
phenyl substituted by
fluorine,
chlorine,
hydroxy,
trifluoromethyl,
alkyl of from one to four carbon atoms,
alkoxy of from one to four carbon atoms,
alkanoyloxy of from two to eight carbon atoms,
2-, 3-, or 4-pyridinyl,
2-, 3-, or 4-pyridinyl-N-oxide,
R2 and R3 are independently
hydrogen,
chlorine,
bromine,
cyano,
trifluoromethyl,
phenyl,
alkyl of from one to four carbon atoms,
carboalkoxy of from two to eight carbon atoms,
R4 is
alkyl of from one to four carbon atoms,
cyclopropyl,
cyclobutyl, or
trifluoromethyl;
or a corresponding lactone ring-opened dihydroxy acid derived therefrom, or a pharmaceutically acceptable salt thereof.
2. A compound in accordance with claim 1 wherein
X is --CH2 CH2 --;
R1 is as defined in claim 1;
R2 and R3 are independently
hydrogen,
chlorine, or
bromine; and
R4 is as defined in claim 1.
3. A compound in accordance with claim 1 wherein
X is --CH2 CH2 --;
R1 is
phenyl,
phenyl substituted by
fluorine,
chlorine,
hydroxy,
trifluoromethyl,
alkyl of from one to four carbon atoms,
alkoxy of from one to four carbon atoms,
alkanoyloxy of from two to eight carbon atoms,
2-, 3-, or 4-pyridinyl,
2-, 3-, or 4-pyridinyl-N-oxide,
R2 and R3 are independently
hydrogen,
chlorine,
bromine; and
R4 is alkyl of from one to four carbon atoms, or trifluoromethyl.
4. A compound in accordance with claim 1 wherein
X is --CH2 CH2 --;
R1 is
phenyl, or
phenyl substituted by
fluorine,
chlorine,
hydroxy,
trifluoromethyl,
alkoxy of from one to four carbon atoms,
alkanoyloxy of from two to eight carbon atoms;
R2 and R3 are independently
hydrogen,
chlorine, or
bromine; and
R4 is isopropyl or trifluoromethyl.
5. A compound in accordance with claim 1 having the name trans-6-[2-[3,4-dichloro-2-(4-fluorophenyl)-5-(1-methylethyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
6. A compound in accordance with claim 1 having the name trans-6-[2-[3,4-dibromo-2-(4-fluorophenyl)-5-(1-methylethyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
7. A compound in accordance with claim 1 having the name trans-6-[2-[2-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrrol-1-yl)ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
8. A compound in accordance with claim 1 having the name trans-dimethyl 2-(4-fluorophenyl)-5-(1-methylethyl)-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3,4-dicarboxylate.
9. A compound in accordance with claim 1 having the name trans-6-[2-[2-(4-fluorophenyl-5-methyl-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
10. A compound in accordance with claim 1 having the name trans-6-[2-[2-(4-fluorophenyl-5-(1-methylethyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
11. A compound in accordance with claim 1 having the name trans-6-[2-[2-cyclopropyl-5-(4-fluorophenyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
12. A compound in accordance with claim 1 having the name trans-6-[2-[2-(1,1-dimethylethyl)-5-(4-fluorophenyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
13. A compound in accordance with claim 1 having the name trans-tetrahydro-4-hydroxy-6-[2-[2-(2-methoxyphenyl)-5-methyl-1H-pyrrol-1-yl]ethyl]-2H-2-one.
14. A compound in accordance with claim 1 having the name trans-tetrahydro-4-hydroxy-6-[2-[2-(2-methoxyphenyl)-5-(1-methylethyl)-1H-pyrrol-1-yl]ethyl]-2H-pyran-2-one.
15. A compound in accordance with claim 1 having the name trans-tetrahydro-4-hydroxy-6-[2-[2-methyl-5-(1-naphthalenyl)-1H-pyrrol-1-yl]ethyl]-2H-pyran-2-one.
16. A compound in accordance with claim 1 having the name trans-6-[2-(2-bicyclo[2.2.1]hep-5-en-2-yl-5-methyl-1H-pyrrol-1-yl)ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
17. A compound in accordance with claim 1 having the name trans-6-[2-[2-(4-fluorophenyl)-5-(1-methylphenyl)-1H-pyrrol-1-yl]propyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
18. A pharmaceutical composition, useful as a hypocholesterolemic agent, comprising a hypocholesterolemic effective amount of a compound in accordance with claim 1 in combination with a pharmaceutically acceptable carrier.
19. A method of treating inhibiting cholesterol biosynthesis in a patient in need of such treatment by administering a pharmaceutical composition in accordance with claim 18.
US06/679,676 1984-09-24 1984-12-10 Trans-6-[2-(substitutedpyrrol-1-yl)alkyl]-pyran-2-one inhibitors of cholesterol synthesis Expired - Fee Related US4647576A (en)

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US06/679,676 US4647576A (en) 1984-09-24 1984-12-10 Trans-6-[2-(substitutedpyrrol-1-yl)alkyl]-pyran-2-one inhibitors of cholesterol synthesis
KR858501374D KR890001449B1 (en) 1984-09-24 1985-02-04 Trans 6-2-(substituted pyrrol-1-yl)alkyl j-pyran 2-one and the process of the preparation thereof
CA000489315A CA1242721A (en) 1984-09-24 1985-08-23 Trans-6-¬2-substituted pyrrol-1-yl)alkyl|-pyran -2- one inhibitors of cholesterol synthesis
NZ213252A NZ213252A (en) 1984-09-24 1985-08-27 Trans-6-((substitutedpyrrol-1-yl)alkyl)-pyran-2-ones and pharmaceutical compositions
AU46867/85A AU573027B2 (en) 1984-09-24 1985-08-29 6-(pyrrol-1-yl)pyran-2-one derivatives
EP85306382A EP0179559A3 (en) 1984-09-24 1985-09-09 Trans-6-[2-(substitutedpyrrol-1-yl)alkyl]-pyran-2-one inhibitors of cholesterol synthesis
ES547055A ES8701756A1 (en) 1984-09-24 1985-09-17 Trans-6- not 2-(substitutedpyrrol-1-yl)alkyl -pyran-2-one inhibitors of cholesterol synthesis
FI853632A FI853632L (en) 1984-09-24 1985-09-20 NYA CHOLESTEROLSYNTHESIS INHIBERANT TRANS-6- / 2- (SUBSTITUERADE PYRROL-1-YL) ALKYL / -PYRAN-2-ONER OCH FOERFARANDE FOER DERAS FRAMSTAELLNING.
GR852297A GR852297B (en) 1984-09-24 1985-09-20
DK430485A DK430485A (en) 1984-09-24 1985-09-23 TRANS-6- (2- (SUBSTITUTED PYRROL-1-YL) ALKYL) -PYRAN-2-ONES, THEIR PREPARATION AND PHARMACEUTICAL USE
KR1019850006950A KR890001050B1 (en) 1984-09-24 1985-09-23 Trans-6-(2-(substituted pyrrol-1-y1)alkyl)-pyron-2 one and their preparation
NO853725A NO853725L (en) 1984-09-24 1985-09-23 PROCEDURE FOR PREPARATION OF TRANS-6- (2- (SUBSTITUTED PYRROL-1-YL) ALKYL) PYRAN-2-ON.
PT81179A PT81179B (en) 1984-09-24 1985-09-24 Trans-6-<2-(substitutedpyrrol-1-yl)alkyl>-pyran-2-one inhibitors of cholesterol synthesis

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Cited By (162)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4735958A (en) * 1986-12-22 1988-04-05 Warner-Lambert Company Trans-6-[2-[2-(substituted-phenyl)-3- (or 4-) heteroaryl-5-substituted-1H-pyrrol-1-yl]-ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one inhibitors of cholesterol biosynthesis
US4761419A (en) * 1987-12-07 1988-08-02 Warner-Lambert Company 6-(((substituted)quinolinyl)ethyl)-and ethenyl)tetrahydro-4-hydroxypyran-2-one inhibitors of cholesterol biosynthesis
US4775681A (en) * 1987-06-18 1988-10-04 Warner-Lambert Company Method of treating fungal infections with trans-6-[2-substitutedpyrrol-1-yl)alkyl]-4-hydroxypyran-2-ones
US4789682A (en) * 1987-03-17 1988-12-06 Merck & Co., Inc. Antihypercholesterolemic compounds
US4822799A (en) * 1988-01-27 1989-04-18 Sandoz Pharm. Corp. Pyrazolopyridine analogs of mevalonolactone and derivatives thereof useful for inhibiting cholesterol biosynthesis in mammals
US4851427A (en) * 1985-10-25 1989-07-25 Sandoz Pharm. Corp. Pyrrole analogs of mevalonolactone, derivatives thereof and pharmaceutical use
US4868185A (en) * 1987-12-10 1989-09-19 Warner-Lambert Company 6-[[Substituted)pyrimidinyl)ethyl]- and ethenyl]tetrahydro-4-hydroxypyran-2-one inhibitors of cholesterol biosynthesis
US4906657A (en) * 1988-12-21 1990-03-06 Warner-Lambert Company Bicyclo heptane and bicyclo octane substituted inhibitors of cholesterol synthesis
US4906624A (en) * 1987-09-08 1990-03-06 Warner-Lambert Company 6-(((Substituted)pyridin-3-yl)alkyl)-and alkenyl)-tetrahydro-4-hydroxypyran-2-one inhibitors of cholesterol biosynthesis
FR2637183A1 (en) * 1988-10-03 1990-04-06 Glaxo Group Ltd NOVEL CHOLESTEROL BIOSYNTHESIS INHIBITORS AND THEIR PREPARATION
US4946841A (en) * 1988-01-09 1990-08-07 Hoechst Aktiengesellachaft Pyridazine 3,5-dihydroxy carboxylic acids and derivatives thereof, the use thereof for hypercholesterolemia
US4957940A (en) * 1988-12-21 1990-09-18 Warner-Lambert Company Bicyclo heptane and bicyclo octane substituted inhibitors of cholesterol synthesis
US4973704A (en) * 1985-10-25 1990-11-27 Sandoz Pharm. Corp. Pyrrolyl intermediates in the synthesis of pyrrole analogs of mevalonolactone and derivatives thereof
US4992462A (en) * 1987-04-14 1991-02-12 Bayer Aktiengesellschaft Substituted pyrroles
US4997837A (en) * 1987-09-08 1991-03-05 Warner-Lambert Company 6-(((substituted)pyridin-3-yl)alkyl)-and alkenyl)-tetrahydro-4-hydroxypyran-2-one inhibitors of cholesterol biosynthesis
US5001255A (en) * 1984-12-04 1991-03-19 Sandoz Pharm. Corp. Idene analogs of mevalonolactone and derivatives thereof
EP0422895A1 (en) * 1989-10-10 1991-04-17 Glaxo Group Limited Chemical compounds
US5010098A (en) * 1987-07-29 1991-04-23 American Cyanamid Company Arylpyrrole insecticidal acaricidal and nematicidal agents and methods for the preparation thereof
US5055484A (en) * 1987-07-10 1991-10-08 Hoechst Aktiengesellschaft 7(1h-pyrrol-3-yl)-substituted 3,5-dihydroxyhept-6-enoic acids, 7-(1h-pyrrol-3-yl)-substituted 3,5-dihyroxyhept-anoic acids, their corresponding delta-lactones and salts, their use as medicaments and pharmaceutical products and intermediates
US5091386A (en) * 1988-09-24 1992-02-25 Hoechst Aktiengesellschaft 7-substituted derivatives of 3,5-dihydroxyhept-6-ynoic acids and corresponding lactones and their use as hypercholeserolemics
US5091378A (en) * 1987-05-22 1992-02-25 E. R. Squibb & Sons, Inc. Phosphorus-containing HMG-CoA reductase inhibitors, new intermediates and method
US5097045A (en) * 1989-02-01 1992-03-17 Warner-Lambert Company Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
US5103024A (en) * 1990-10-17 1992-04-07 Warner-Lambert Company Process for the synthesis of (4r-cis)-1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate
US5124482A (en) * 1988-02-22 1992-06-23 Warner-Lambert Company Process for trans-6-(2-substituted-pyrrol-1-yl)alkyl)pyran-2-one inhibitors of cholesterol synthesis
US5149837A (en) * 1988-02-22 1992-09-22 Warner-Lambert Company Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
US5155251A (en) * 1991-10-11 1992-10-13 Warner-Lambert Company Process for the synthesis of (5R)-1,1-dimethylethyl-6-cyano-5-hydroxy-3-oxo-hexanoate
US5216174A (en) * 1988-02-22 1993-06-01 Warner-Lambert Co. Process for trans-6-[12-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
US5248793A (en) * 1990-10-17 1993-09-28 Warner-Lambert Company Process for the synthesis of (4R-cis)-1,1-dimethylethyl 6-iodomethyl or 6-(phenyl-substituted)sulfonyloxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate
US5280126A (en) * 1988-02-22 1994-01-18 Warner-Lambert Company Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
US5298627A (en) * 1993-03-03 1994-03-29 Warner-Lambert Company Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
US5310938A (en) * 1987-07-29 1994-05-10 American Cyanamid Company Substituted arylpyrrole compounds
US5354772A (en) * 1982-11-22 1994-10-11 Sandoz Pharm. Corp. Indole analogs of mevalonolactone and derivatives thereof
US5449789A (en) * 1992-11-30 1995-09-12 American Cyanamid Company Debrominative chlorination of pyrroles
US5506219A (en) * 1988-08-29 1996-04-09 E. R. Squibb & Sons, Inc. Pyridine anchors for HMG-CoA reductase inhibitors
WO2000028981A3 (en) * 1998-11-13 2000-11-09 Nymox Corp Methods for treating, preventing, and reducing the risk of the onset of alzheimer's disease using an hmg coa reductase inhibitor
US6177121B1 (en) 1997-09-29 2001-01-23 Purdue Research Foundation Composition and method for producing low cholesterol eggs
US6277833B1 (en) * 1992-12-21 2001-08-21 Bayer Aktiengesellschaft Substituted triols
US20030157671A1 (en) * 2001-11-02 2003-08-21 Ramakrishnan Chidambaram Process for the preparation of aniline-derived thyroid receptor ligands
US20030166724A1 (en) * 2001-12-07 2003-09-04 Hangeland Jon J. Phenyl naphthol ligands for thyroid hormone receptor
US20030195157A1 (en) * 2001-10-18 2003-10-16 Natarajan Sesha Iyer Human glucagon-like-peptide-1 mimics and their use in the treatment of diabetes and related conditions
US20030224058A1 (en) * 2002-05-24 2003-12-04 Elan Pharma International, Ltd. Nanoparticulate fibrate formulations
US20030225091A1 (en) * 2001-11-16 2003-12-04 Magnin David R. Dual inhibitors of adipocyte fatty acid binding protein and keratinocyte fatty acid binding protein
US20030232796A1 (en) * 2002-06-10 2003-12-18 Elan Pharma International, Ltd. Nanoparticulate polycosanol formulations & novel polycosanol combinations
US20040002495A1 (en) * 2002-05-20 2004-01-01 Philip Sher Lactam glycogen phosphorylase inhibitors and method of use
US20040058009A1 (en) * 2002-05-24 2004-03-25 Elan Pharma International, Ltd. Nanoparticulate fibrate formulations
US20040102490A1 (en) * 2000-11-21 2004-05-27 Lieven Meerpoel Biphenylcarboxamides useful as lipid lowering agents
US6747048B2 (en) 2002-05-08 2004-06-08 Bristol-Myers Squibb Company Pyridine-based thyroid receptor ligands
US20040127423A1 (en) * 2001-10-18 2004-07-01 Natarajan Sesha Iyer Human glucagon-like-peptide-1 mimics and their use in the treatment of diabetes and related conditions
US20040132771A1 (en) * 2002-12-20 2004-07-08 Pfizer Inc Compositions of choleseteryl ester transfer protein inhibitors and HMG-CoA reductase inhibitors
US20040142938A1 (en) * 2002-11-14 2004-07-22 Sher Philip M. Triglyceride and triglyceride-like prodrugs of glycogen phosphorylase inhibiting compounds
US6774112B2 (en) 2001-04-11 2004-08-10 Bristol-Myers Squibb Company Amino acid complexes of C-aryl glucosides for treatment of diabetes and method
US20040176425A1 (en) * 2003-01-24 2004-09-09 Washburn William N. Cycloalkyl containing anilide ligands for the thyroid receptor
US20040180940A1 (en) * 2003-01-24 2004-09-16 Washburn William N. Substituted anilide ligands for the thyroid receptor
US20040242673A1 (en) * 2003-05-16 2004-12-02 Ambit Biosciences Corporation Heterocyclic compounds and uses thereof
US20040248972A1 (en) * 2003-05-16 2004-12-09 Ambit Biosciences Corporation Compounds and uses thereof
US20040254391A1 (en) * 2001-07-03 2004-12-16 Blacker Andrew John Process for the preparation of nitrile compounds
US20040259919A1 (en) * 2002-10-23 2004-12-23 Magnin David R. Glycinenitrile-based inhibitors of dipeptidyl peptidase IV and methods
US20040266831A1 (en) * 2003-06-11 2004-12-30 Robinson Leslie A. Modulators of the glucocorticoid receptor and method
US20050004184A1 (en) * 2003-04-18 2005-01-06 Ryono Denis E. Thyroid receptor ligands
US20050038020A1 (en) * 2003-08-01 2005-02-17 Hamann Lawrence G. Adamantylglycine-based inhibitors of dipeptidyl peptidase IV and methods
US20050042284A1 (en) * 2003-07-11 2005-02-24 Myriad Genetics, Incorporated Pharmaceutical methods, dosing regimes and dosage forms for the treatment of Alzheimer's disease
US20050171207A1 (en) * 2003-09-26 2005-08-04 Myriad Genetics, Incorporated Method and composition for combination treatment of neurodegenerative disorders
US20050182125A1 (en) * 2003-05-16 2005-08-18 Ambit Biosciences Corporation Pyrrole compounds and uses thereof
WO2005087234A1 (en) 2004-03-05 2005-09-22 The Trustees Of The University Of Pennsylvania Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side-effects
US20050252144A1 (en) * 2004-04-29 2005-11-17 Macdonald Robert A Veneers for walls, retaining walls and the like
US20050288375A1 (en) * 2003-02-05 2005-12-29 Myriad Genetics, Incorporated Method and composition for treating neurodegenerative disorders
US20060004222A1 (en) * 2004-07-02 2006-01-05 Arvind Mathur Process for the preparation of amino acids useful in the preparation of peptide receptor modulators
US20060019269A1 (en) * 2002-10-17 2006-01-26 Decode Genetics, Inc. Susceptibility gene for myocardial infarction, stroke, and PAOD, methods of treatment
US20060063722A1 (en) * 2004-09-23 2006-03-23 William Washburn C-aryl glucoside SGLT2 inhibitors and method
US20060079556A1 (en) * 2004-10-12 2006-04-13 Sher Philip M N-sulfonylpiperidine cannabinoid receptor 1 antagonists
US20060141035A1 (en) * 1997-12-12 2006-06-29 Andrx Labs Llc HMG-COA reductase inhibitor extended release formulation
US20060142576A1 (en) * 2004-12-29 2006-06-29 Wei Meng Pyrimidine-based inhibitors of dipeptidyl peptidase IV and methods
US20060155126A1 (en) * 2005-01-12 2006-07-13 Chongqing Sun Bicyclic heterocycles as cannabinoid receptor modulators
US20060154955A1 (en) * 2005-01-12 2006-07-13 Chongqing Sun Bicyclic heterocycles as cannabinoid receptor modulators
US20060166999A1 (en) * 2000-06-21 2006-07-27 Bayer Aktiengesellschaft Use of microsomal triglyceride transfer protein (MTP) inhibitors for reducing the number of postprandial triglyceride-rich lipoprotein particles (PPTRL)
US20060178377A1 (en) * 2004-12-29 2006-08-10 Wei Meng Azolopyrimidine-based inhibitors of dipeptidyl peptidase IV and methods
US20060194772A1 (en) * 2001-06-28 2006-08-31 Pfizer Inc Triamide-substituted heterobicyclic compounds
US20060287242A1 (en) * 2004-07-02 2006-12-21 Ewing William R Human glucagon-like-peptide-1 modulators and their use in treatment of diabetes and related conditions
US20060287322A1 (en) * 2005-06-17 2006-12-21 Chongqing Sun Bicyclic heterocycles as cannabinoind-1 receptor modulators
US20060287323A1 (en) * 2005-06-17 2006-12-21 Ewing William R Azabicyclic heterocycles as cannabinoid receptor modulators
US20060287324A1 (en) * 2005-06-17 2006-12-21 Chongqing Sun Bicyclic heterocycles as cannabinoid-1 receptor modulators
US20060287341A1 (en) * 2005-06-17 2006-12-21 Gang Wu Triazolopyrimidine cannabinoid receptor 1 antagonists
US20060287342A1 (en) * 2005-06-17 2006-12-21 Mikkilineni Amarendra B Triazolopyrimidine heterocycles as cannabinoid receptor modulators
US20070004772A1 (en) * 2005-06-17 2007-01-04 Chongqing Sun Triazolopyridine cannabinoid receptor 1 antagonists
EP1743630A2 (en) 1997-07-31 2007-01-17 Kos Pharmaceuticals, Inc. Pharmaceutical combination
US20070015832A1 (en) * 2005-07-14 2007-01-18 Myriad Genetics, Incorporated Methods of treating overactive bladder and urinary incontinence
US20070021346A1 (en) * 2005-05-26 2007-01-25 Ewing William R N-terminally modified GLP-1 receptor modulators
US20070042034A1 (en) * 2005-07-22 2007-02-22 Myriad Genetics, Incorporated High drug load formulations and dosage forms
US20070088089A1 (en) * 2005-10-18 2007-04-19 Wisler Gerald L Methods for treating disorders associated with hyperlipidemia in a mammal
US20070093509A1 (en) * 2005-10-26 2007-04-26 Bristol-Myers Squibb Company Non-basic melanin concentrating hormone receptor-1 antagonists
WO2007053819A2 (en) 2005-10-31 2007-05-10 Bristol-Myers Squibb Company Pyrrolidinyl beta-amino amide-based inhibitors of dipeptidyl peptidase iv and methods
US7220859B2 (en) 2005-01-12 2007-05-22 Bristol-Myers Squibb Company Bicyclic heterocycles as cannabinoid receptor modulators
WO2007073503A2 (en) 2005-12-21 2007-06-28 Bristol-Myers Squibb Company Indane modulators of glucocorticoid receptor, ap-1, and/or nf-kb activity and use thereof
US20070185097A1 (en) * 2006-02-06 2007-08-09 Bristol-Myers Squibb Company Melanin concentrating hormone receptor-1 antagonists
US20070202180A1 (en) * 2006-02-28 2007-08-30 Elan Pharma International Limited Nanoparticulate carverdilol formulations
US20070232589A1 (en) * 2004-08-11 2007-10-04 Myriad Genetics, Incorporated Pharmaceutical Composition And Method For Treating Neurodegenerative Disorders
US20070232672A1 (en) * 2004-08-11 2007-10-04 Myriad Genetics, Incorporated Pharmaceutical Composition And Method For Treating Neurodegenerative Disorders
US20070232656A1 (en) * 2004-08-11 2007-10-04 Myriad Genetics, Incorporated Pharmaceutical Composition And Method For Treating Neurodegenerative Disorders
US20070238770A1 (en) * 2006-04-05 2007-10-11 Bristol-Myers Squibb Company Process for preparing novel crystalline forms of peliglitazar, novel stable forms produced therein and formulations
US20070238669A1 (en) * 2006-01-11 2007-10-11 Bristol-Myers Squibb Company Human glucagon-like-peptide-1 modulators and their use in the treatment of diabetes related conditions
US20070253905A1 (en) * 2000-04-13 2007-11-01 Mayo Foundation For Medical Education Abeta42 LOWERING AGENTS
US20070264348A1 (en) * 2002-05-24 2007-11-15 Elan Pharma International, Ltd. Nanoparticulate fibrate formulations
WO2007140191A2 (en) 2006-05-23 2007-12-06 Theracos, Inc. Glucose transport inhibitors and methods of use
US20070280917A1 (en) * 2005-03-30 2007-12-06 Decode Genetics, Inc. Susceptibility gene for myocardial infarction, stroke, and PAOD; methods of treatment
WO2007139589A1 (en) 2006-05-26 2007-12-06 Bristol-Myers Squibb Company Sustained release glp-1 receptor modulators
US20070293538A1 (en) * 2004-04-13 2007-12-20 Myriad Genetics, Incorporated Pharmaceutical Composition And Methods For Treating Neurodegenerative Disorders
WO2008006043A2 (en) 2006-07-07 2008-01-10 Bristol-Myers Squibb Company 1,3-oxazole derivatives useful as anti-atherosclerotic, anti-dyslipidemic, anti-diabetic and anti-obesity agents
US20080020046A1 (en) * 2004-01-23 2008-01-24 Fournier Laboratories Ireland Limited Pharmaceutical Formulations Comprising Metformin And A Fibrate, And Processes For Obtaining Them
US20080033045A1 (en) * 2006-07-07 2008-02-07 Myriad Genetics, Incorporated Treatment of psychiatric disorders
US20080044326A1 (en) * 2006-07-04 2008-02-21 Esencia Co., Ltd. Sterilizer for baby products
US20080081813A1 (en) * 2001-04-06 2008-04-03 Lieven Meerpoel Lipid Lowering Biphenylcarboxamides
WO2008057862A2 (en) 2006-11-01 2008-05-15 Bristol-Myers Squibb Company MODULATORS OF GLUCOCORTICOID RECEPTOR, AP-1, AND/OR NF-&kappav;B ACTIVITY AND USE THEREOF
US20080125412A1 (en) * 2000-09-04 2008-05-29 Lieven Meerpoel Polyarylcarboxamides useful as lipid lowering agents
US20080139457A1 (en) * 2005-09-16 2008-06-12 Virginia Commonwealth University Therapeutic compositions comprising chorionic gonadotropins and HMG CoA reductase inhibitors
US20080161279A1 (en) * 2006-12-21 2008-07-03 Wisler Gerald L Methods of Treating Obesity
US20080200459A1 (en) * 2005-01-18 2008-08-21 Bristol-Myers Squibb Company Tetrahydroquinoline cannabinoid receptor modulators
EP1961419A1 (en) 2002-12-20 2008-08-27 Pfizer Products Inc. Dosage forms comprising a CETP inhibitor and an HMG-CoA reductase inhibitor
US20080213378A1 (en) * 1998-10-01 2008-09-04 Elan Pharma International, Ltd. Nanoparticulate statin formulations and novel statin combinations
US20080241070A1 (en) * 2000-09-21 2008-10-02 Elan Pharma International Ltd. Fenofibrate dosage forms
US20080287529A1 (en) * 2007-05-18 2008-11-20 Bristol-Myers Squibb Company Crystal structures of sglt2 inhibitors and processes for preparing same
US20080293750A1 (en) * 2002-10-17 2008-11-27 Anna Helgadottir Susceptibility Gene for Myocardial Infarction, Stroke, Paod and Methods of Treatment
US20090030046A1 (en) * 2007-07-27 2009-01-29 Bristol-Myers Squibb Company Novel glucokinase activators and methods of using same
US20090054303A1 (en) * 2007-04-20 2009-02-26 Bristol-Myers Squibb Company Crystal forms of saxagliptin and processes for preparing same
US20090069275A1 (en) * 2006-02-17 2009-03-12 Rocca Jose G Low flush niacin formulation
USRE40667E1 (en) 1989-07-21 2009-03-17 Warner-Lambert Company Llc [R-(R*R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, its lactone form and salts thereof
US7521557B2 (en) 2005-05-20 2009-04-21 Bristol-Myers Squibb Company Pyrrolopyridine-based inhibitors of dipeptidyl peptidase IV and methods
US7534763B2 (en) 2004-07-02 2009-05-19 Bristol-Myers Squibb Company Sustained release GLP-1 receptor modulators
US20090156623A1 (en) * 2002-08-12 2009-06-18 Lieven Meerpoel N-aryl piperidine substituted biphenylcarboxamides
US20090270409A1 (en) * 2007-09-20 2009-10-29 Irm Llc Compounds and compositions as modulators of gpr119 activity
US20090298794A1 (en) * 2008-05-29 2009-12-03 Bristol-Myers Squibb Company Hydroxy substituted thieno pyrimidinones as melanin concentrating hormone receptor-1 antagonists
US20090326013A1 (en) * 2007-03-01 2009-12-31 Curt Hendrix Isomers of inositol niacinate and uses thereof
WO2010009243A1 (en) 2008-07-15 2010-01-21 Theracos, Inc. Deuterated benzylbenzene derivatives and methods of use
WO2010093601A1 (en) 2009-02-10 2010-08-19 Metabasis Therapeutics, Inc. Novel sulfonic acid-containing thyromimetics, and methods for their use
US20100216863A1 (en) * 2004-01-30 2010-08-26 Decode Genetics Ehf. Susceptibility Gene for Myocardial Infarction, Stroke, and PAOD; Methods of Treatment
WO2010111665A1 (en) 2009-03-27 2010-09-30 Bristol-Myers Squibb Company Methods for preventing major adverse cardiovascular events with dpp-iv inhibitors
US20110003759A1 (en) * 2007-07-06 2011-01-06 Bristol-Myers Squibb Company Non-basic melanin concentrating hormone receptor-1 antagonists and methods
WO2011014520A2 (en) 2009-07-29 2011-02-03 Irm Llc Compounds and compositions as modulators of gpr119 activity
US20110027371A1 (en) * 1998-10-01 2011-02-03 Elan Pharma International Limited Nanoparticulate statin formulations and novel statin combinations
WO2011044001A1 (en) 2009-10-09 2011-04-14 Irm Llc Compounds and compositions as modulators of gpr119 activity
WO2011060290A2 (en) 2009-11-13 2011-05-19 Bristol-Myer Squibb Company Immediate release tablet formulations
WO2011060256A2 (en) 2009-11-13 2011-05-19 Bristol-Myers Squibb Company Bilayer tablet formulations
WO2011060255A1 (en) 2009-11-13 2011-05-19 Bristol-Myers Squibb Company Reduced mass metformin formulations
WO2011067306A1 (en) 2009-12-03 2011-06-09 Novartis Ag Cyclohexane derivatives as inhibitors of acetyl-coa carboxylase (acc)
WO2011109333A1 (en) 2010-03-02 2011-09-09 Lexicon Pharmaceuticals, Inc. 6 -benzylphenyl- 2 - sulfurterahydropyran-3, 4, 5 -triol derivatives as inhibitors of sodium -glucose cotrans porters 1 and 2 for use in diabetic patients
WO2011130459A1 (en) 2010-04-14 2011-10-20 Bristol-Myers Squibb Company Novel glucokinase activators and methods of using same
WO2011153953A1 (en) 2010-06-12 2011-12-15 Theracos, Inc. Crystalline form of benzylbenzene sglt2 inhibitor
WO2012006398A2 (en) 2010-07-09 2012-01-12 Bhv Pharma, Inc. Combination immediate/delayed release delivery system for short half-life pharmaceuticals including remogliflozin
WO2012013716A1 (en) 2010-07-29 2012-02-02 Novartis Ag Bicyclic acetyl-coa carboxylase inhibitors
EP2428516A1 (en) 2003-11-19 2012-03-14 Metabasis Therapeutics, Inc. Novel phosphorus-containing thyromimetics
US8158677B2 (en) 2007-06-01 2012-04-17 The Trustees Of Princeton University Treatment of viral infections by modulation of host cell metabolic pathways
EP2457918A2 (en) 2006-06-28 2012-05-30 Bristol-Myers Squibb Company Crystalline solvates and complexes of (1s)-1,5-anhydro-1-c-(3-((phenyl) methyl) phenyl)-d-glucitol derivatives with amino acids as SGLT2 inhibitors for the treatment of diabetes
WO2012094293A1 (en) 2011-01-05 2012-07-12 Lexicon Pharmaceuticals, Inc. Compositions comprising and methods of using inhibitors of sodium-glucose cotransporters 1 and 2
EP2527337A1 (en) 2005-04-14 2012-11-28 Bristol-Myers Squibb Company Inhibitors of 11-beta hydroxysteroid dehydrogenase type I
WO2014052619A1 (en) 2012-09-27 2014-04-03 Irm Llc Piperidine derivatives and compositions as modulators of gpr119 activity
WO2014081660A1 (en) 2012-11-20 2014-05-30 Lexicon Pharmaceuticals, Inc. Inhibitors of sodium glucose cotransporter 1
CN104356118A (en) * 2014-10-17 2015-02-18 上海应用技术学院 Polysubstitution pyrroles pitavastatin lactone dewatering compound and application thereof
WO2015027021A1 (en) 2013-08-22 2015-02-26 Bristol-Myers Squibb Company Imide and acylurea derivatives as modulators of the glucocorticoid receptor
WO2016176656A2 (en) 2015-04-30 2016-11-03 President And Fellows Of Harvard College Anti-ap2 antibodies and antigen binding agents to treat metabolic disorders
EP3318562A2 (en) 2007-08-23 2018-05-09 Theracos Sub, LLC Benzylbenzene derivatives and methods of use
WO2020016335A1 (en) 2018-07-19 2020-01-23 Astrazeneca Ab Methods of treating hfpef employing dapagliflozin and compositions comprising the same
WO2020068661A1 (en) 2018-09-26 2020-04-02 Lexicon Pharmaceuticals, Inc. Crystalline forms of n-(1 -((2-(dimethylamino)ethyl)amino)-2-m ethyl-1 -oopropan-2-yl)-4-(4-(2-methyl-5- (2s,3r,4r,5s,6r)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2h-pyran-2-yl)benzyl) phenl)butanamide and methods of their synthesis
EP4245299A2 (en) 2007-03-22 2023-09-20 Astrazeneca AB Pharmaceutical formulations containing dapagliflozin propylene glycol hydrate

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4681893A (en) * 1986-05-30 1987-07-21 Warner-Lambert Company Trans-6-[2-(3- or 4-carboxamido-substituted pyrrol-1-yl)alkyl]-4-hydroxypyran-2-one inhibitors of cholesterol synthesis
DE3722809A1 (en) * 1987-07-10 1989-01-19 Hoechst Ag 3-DESMETHYL-4-FLUOR-MEVALONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, PHARMACEUTICAL PREPARATIONS BASED ON THESE COMPOUNDS, THEIR USE AND INTERMEDIATE PRODUCTS
DE3817808A1 (en) * 1987-07-21 1989-02-02 Bayer Ag METHOD FOR PRODUCING 2-SUBSTITUTED PYRROL
US5185328A (en) * 1987-08-20 1993-02-09 Nissan Chemical Industries Ltd. Quinoline type mevalonolactones useful for treating hyperlipidemia, hyperlipoproteinemia or atherosclerosis
CA1336714C (en) * 1987-08-20 1995-08-15 Yoshihiro Fujikawa Quinoline type mevalonolactone inhibitors of cholesterol biosynthesis
JP2569746B2 (en) * 1987-08-20 1997-01-08 日産化学工業株式会社 Quinoline mevalonolactones
GB8728314D0 (en) * 1987-12-03 1988-01-06 May & Baker Ltd New compositions of matter
KR890011876A (en) * 1988-01-27 1989-08-23 메이 앤드 베이커 리미팃드 Novel isoquinoline derivatives preparation method thereof and pharmaceutical composition containing the same
US5003080A (en) * 1988-02-22 1991-03-26 Warner-Lambert Company Process for trans-6-(2-(substituted-pyrrol-1-yl)alkyl)pryan-2-one inhibitors of cholesterol synthesis
IT1226726B (en) * 1988-07-29 1991-02-05 Zambon Spa ACTIVE COMPOUNDS AS CHOLESTEROL BIOSYNTHESIS INHIBITORS.
US5196440A (en) * 1988-07-29 1993-03-23 Zambon Group S.P.A. Compounds active as inhibitors of the cholesterol biosynthesis
IT1237792B (en) * 1989-12-21 1993-06-17 Zambon Spa ACTIVE COMPOUNDS AS INHIBITORS OF THE HMG-COA REDUCTASE ENZYME
US7056906B2 (en) 2001-09-21 2006-06-06 Schering Corporation Combinations of hormone replacement therapy composition(s) and sterol absorption inhibitor(s) and treatments for vascular conditions in post-menopausal women
CA2517571C (en) 2003-03-07 2011-07-05 Schering Corporation Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof
ATE418551T1 (en) 2003-03-07 2009-01-15 Schering Corp SUBSTITUTED AZETIDINONE DERIVATIVES, THEIR PHARMACEUTICAL FORMULATIONS AND THEIR USE IN THE TREATMENT OF HYPERCHOLESTEROLEMIA

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3983140A (en) * 1974-06-07 1976-09-28 Sankyo Company Limited Physiologically active substances
US4198425A (en) * 1977-05-24 1980-04-15 Sankyo Company Limited Mevalonolactone derivatives
US4219560A (en) * 1978-04-17 1980-08-26 Sandoz, Inc. Piperidine and pyrrolidine alcohols
US4248889A (en) * 1978-10-30 1981-02-03 Sankyo Company Limited 3,5-Dihydroxypentanoic ester derivatives having antihyperlipaemic activity
US4255444A (en) * 1978-10-30 1981-03-10 Sankyo Company Limited 4-Hydroxy-2-pyrone derivatives having antihyperlipaemic activity
US4308378A (en) * 1980-09-02 1981-12-29 Merck & Co., Inc. Cis/trans isomerization of 6-(substituted-aryl-ethenyl)-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-ones
US4343811A (en) * 1979-03-13 1982-08-10 Boehringer Ingelheim Gmbh 2[3-(4-Chlorophenyl)-1,2-dimethyl-1H-indol-5-yloxy]-2-methyl propanoic acid and hyperlipidemic or atheosclerotic use thereof
US4351844A (en) * 1980-02-04 1982-09-28 Merck & Co., Inc. Hypocholesterolemic hydrogenation products and process of preparation
US4375425A (en) * 1980-12-08 1983-03-01 Texaco Inc. Catalyst for the production of a hydrogen-rich gas
US4376863A (en) * 1981-08-21 1983-03-15 Merck & Co., Inc. Hypocholesterolemic fermentation products
BE895445A (en) * 1981-12-23 1983-04-15 Endo Akira DIHYDRO- AND TETRAHYDROMONACOLINS L, THEIR PREPARATION PROCESS AND THEIR APPLICATION IN TJERAPEUTICS
US4440927A (en) * 1981-06-19 1984-04-03 Merck & Co., Inc. Process for preparing inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase via a chiral synthon

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ194557A (en) * 1979-08-17 1984-09-28 Merck & Co Inc Substituted pyranone derivatives;dihydroxy acids therefrom;pharmaceutical compositions
EP0068038B1 (en) * 1981-06-29 1985-09-25 Merck & Co. Inc. (+)-(4r,6s)-(e)-6-(2-(4'-fluoro-3,3',5-trimethyl-(1,1'-biphenyl)-2-yl)ethenyl)-3,4,5,6-tetrahydro-4-hydroxy-2h-pyran-2-one, a process for preparing and a pharmaceutical composition containing the same
KR900001212B1 (en) * 1985-10-25 1990-02-28 산도즈 파마슈티칼스 코오포레이숀 Mevalonolactones and their derivatives and process and pharmaceutical use, thereof

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3983140A (en) * 1974-06-07 1976-09-28 Sankyo Company Limited Physiologically active substances
US4198425A (en) * 1977-05-24 1980-04-15 Sankyo Company Limited Mevalonolactone derivatives
US4219560A (en) * 1978-04-17 1980-08-26 Sandoz, Inc. Piperidine and pyrrolidine alcohols
US4248889A (en) * 1978-10-30 1981-02-03 Sankyo Company Limited 3,5-Dihydroxypentanoic ester derivatives having antihyperlipaemic activity
US4255444A (en) * 1978-10-30 1981-03-10 Sankyo Company Limited 4-Hydroxy-2-pyrone derivatives having antihyperlipaemic activity
US4343811A (en) * 1979-03-13 1982-08-10 Boehringer Ingelheim Gmbh 2[3-(4-Chlorophenyl)-1,2-dimethyl-1H-indol-5-yloxy]-2-methyl propanoic acid and hyperlipidemic or atheosclerotic use thereof
US4351844A (en) * 1980-02-04 1982-09-28 Merck & Co., Inc. Hypocholesterolemic hydrogenation products and process of preparation
US4308378A (en) * 1980-09-02 1981-12-29 Merck & Co., Inc. Cis/trans isomerization of 6-(substituted-aryl-ethenyl)-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-ones
US4375425A (en) * 1980-12-08 1983-03-01 Texaco Inc. Catalyst for the production of a hydrogen-rich gas
US4440927A (en) * 1981-06-19 1984-04-03 Merck & Co., Inc. Process for preparing inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase via a chiral synthon
US4376863A (en) * 1981-08-21 1983-03-15 Merck & Co., Inc. Hypocholesterolemic fermentation products
BE895445A (en) * 1981-12-23 1983-04-15 Endo Akira DIHYDRO- AND TETRAHYDROMONACOLINS L, THEIR PREPARATION PROCESS AND THEIR APPLICATION IN TJERAPEUTICS

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Hulcher, Archives of Biochemistry and Biophysics, 146, (1971), pp. 422 427. *
Hulcher, Archives of Biochemistry and Biophysics, 146, (1971), pp. 422-427.

Cited By (296)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5354772A (en) * 1982-11-22 1994-10-11 Sandoz Pharm. Corp. Indole analogs of mevalonolactone and derivatives thereof
US5001255A (en) * 1984-12-04 1991-03-19 Sandoz Pharm. Corp. Idene analogs of mevalonolactone and derivatives thereof
US4851427A (en) * 1985-10-25 1989-07-25 Sandoz Pharm. Corp. Pyrrole analogs of mevalonolactone, derivatives thereof and pharmaceutical use
US4973704A (en) * 1985-10-25 1990-11-27 Sandoz Pharm. Corp. Pyrrolyl intermediates in the synthesis of pyrrole analogs of mevalonolactone and derivatives thereof
US4735958A (en) * 1986-12-22 1988-04-05 Warner-Lambert Company Trans-6-[2-[2-(substituted-phenyl)-3- (or 4-) heteroaryl-5-substituted-1H-pyrrol-1-yl]-ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one inhibitors of cholesterol biosynthesis
US4789682A (en) * 1987-03-17 1988-12-06 Merck & Co., Inc. Antihypercholesterolemic compounds
US4992462A (en) * 1987-04-14 1991-02-12 Bayer Aktiengesellschaft Substituted pyrroles
US5091378A (en) * 1987-05-22 1992-02-25 E. R. Squibb & Sons, Inc. Phosphorus-containing HMG-CoA reductase inhibitors, new intermediates and method
US5276021A (en) * 1987-05-22 1994-01-04 E. R. Squibb & Sons, Inc. Phosphorus-containing HMG-COA reductase inhibitors, new intermediates and method
US4775681A (en) * 1987-06-18 1988-10-04 Warner-Lambert Company Method of treating fungal infections with trans-6-[2-substitutedpyrrol-1-yl)alkyl]-4-hydroxypyran-2-ones
US5055484A (en) * 1987-07-10 1991-10-08 Hoechst Aktiengesellschaft 7(1h-pyrrol-3-yl)-substituted 3,5-dihydroxyhept-6-enoic acids, 7-(1h-pyrrol-3-yl)-substituted 3,5-dihyroxyhept-anoic acids, their corresponding delta-lactones and salts, their use as medicaments and pharmaceutical products and intermediates
US5010098A (en) * 1987-07-29 1991-04-23 American Cyanamid Company Arylpyrrole insecticidal acaricidal and nematicidal agents and methods for the preparation thereof
US5310938A (en) * 1987-07-29 1994-05-10 American Cyanamid Company Substituted arylpyrrole compounds
US4906624A (en) * 1987-09-08 1990-03-06 Warner-Lambert Company 6-(((Substituted)pyridin-3-yl)alkyl)-and alkenyl)-tetrahydro-4-hydroxypyran-2-one inhibitors of cholesterol biosynthesis
US4997837A (en) * 1987-09-08 1991-03-05 Warner-Lambert Company 6-(((substituted)pyridin-3-yl)alkyl)-and alkenyl)-tetrahydro-4-hydroxypyran-2-one inhibitors of cholesterol biosynthesis
US4761419A (en) * 1987-12-07 1988-08-02 Warner-Lambert Company 6-(((substituted)quinolinyl)ethyl)-and ethenyl)tetrahydro-4-hydroxypyran-2-one inhibitors of cholesterol biosynthesis
US4868185A (en) * 1987-12-10 1989-09-19 Warner-Lambert Company 6-[[Substituted)pyrimidinyl)ethyl]- and ethenyl]tetrahydro-4-hydroxypyran-2-one inhibitors of cholesterol biosynthesis
US4946841A (en) * 1988-01-09 1990-08-07 Hoechst Aktiengesellachaft Pyridazine 3,5-dihydroxy carboxylic acids and derivatives thereof, the use thereof for hypercholesterolemia
US4822799A (en) * 1988-01-27 1989-04-18 Sandoz Pharm. Corp. Pyrazolopyridine analogs of mevalonolactone and derivatives thereof useful for inhibiting cholesterol biosynthesis in mammals
US5216174A (en) * 1988-02-22 1993-06-01 Warner-Lambert Co. Process for trans-6-[12-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
US5124482A (en) * 1988-02-22 1992-06-23 Warner-Lambert Company Process for trans-6-(2-substituted-pyrrol-1-yl)alkyl)pyran-2-one inhibitors of cholesterol synthesis
US5149837A (en) * 1988-02-22 1992-09-22 Warner-Lambert Company Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
US5280126A (en) * 1988-02-22 1994-01-18 Warner-Lambert Company Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
US5686433A (en) * 1988-08-29 1997-11-11 E.R. Squibb & Sons, Inc. Quinoline and pyridine anchors for HMG-CoA reductase inhibitors
US5691322A (en) * 1988-08-29 1997-11-25 E.R. Squibb & Sons, Inc. Quinoline and pyridine anchors for HMG-CoA reductase inhibitors
US5506219A (en) * 1988-08-29 1996-04-09 E. R. Squibb & Sons, Inc. Pyridine anchors for HMG-CoA reductase inhibitors
US5091386A (en) * 1988-09-24 1992-02-25 Hoechst Aktiengesellschaft 7-substituted derivatives of 3,5-dihydroxyhept-6-ynoic acids and corresponding lactones and their use as hypercholeserolemics
GR890100634A (en) * 1988-10-03 1990-11-29 Glaxo Group Ltd Imidazole derivatives
BE1003007A3 (en) * 1988-10-03 1991-10-22 Glaxo Group Ltd NOVEL INHIBITORS OF THE BIOSYNTHESIS OF CHOLESTEROL AND THEIR PREPARATION.
FR2637183A1 (en) * 1988-10-03 1990-04-06 Glaxo Group Ltd NOVEL CHOLESTEROL BIOSYNTHESIS INHIBITORS AND THEIR PREPARATION
US5120848A (en) * 1988-10-03 1992-06-09 Glaxo Group Limited Imidazole derivatives
US5013749A (en) * 1988-10-03 1991-05-07 Glaxo Group Limited Imidazole derivatives and their use as hypercholesterolemia and hyperlipoproteinemia agents
US4906657A (en) * 1988-12-21 1990-03-06 Warner-Lambert Company Bicyclo heptane and bicyclo octane substituted inhibitors of cholesterol synthesis
US4957940A (en) * 1988-12-21 1990-09-18 Warner-Lambert Company Bicyclo heptane and bicyclo octane substituted inhibitors of cholesterol synthesis
US5097045A (en) * 1989-02-01 1992-03-17 Warner-Lambert Company Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
USRE40667E1 (en) 1989-07-21 2009-03-17 Warner-Lambert Company Llc [R-(R*R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, its lactone form and salts thereof
US5112819A (en) * 1989-10-10 1992-05-12 Glaxo Group Limited Imidazole derivatives, pharmaceutical compositions and use
EP0422895A1 (en) * 1989-10-10 1991-04-17 Glaxo Group Limited Chemical compounds
US5248793A (en) * 1990-10-17 1993-09-28 Warner-Lambert Company Process for the synthesis of (4R-cis)-1,1-dimethylethyl 6-iodomethyl or 6-(phenyl-substituted)sulfonyloxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate
US5103024A (en) * 1990-10-17 1992-04-07 Warner-Lambert Company Process for the synthesis of (4r-cis)-1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate
US5155251A (en) * 1991-10-11 1992-10-13 Warner-Lambert Company Process for the synthesis of (5R)-1,1-dimethylethyl-6-cyano-5-hydroxy-3-oxo-hexanoate
US5449789A (en) * 1992-11-30 1995-09-12 American Cyanamid Company Debrominative chlorination of pyrroles
US6277833B1 (en) * 1992-12-21 2001-08-21 Bayer Aktiengesellschaft Substituted triols
US5510488A (en) * 1993-03-03 1996-04-23 Warner-Lambert Company Process for trans-6- 2-(substituted-pyrrol-1-yl)alkyl!pyran-2-one inhibitors of cholesterol synthesis
US5489690A (en) * 1993-03-03 1996-02-06 Warner-Lambert Company Process for trans-6[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
US5489691A (en) * 1993-03-03 1996-02-06 Warner-Lambert Company Process for trans-6-(2-(substituted-pyrrol-1-yl)alkyl)pyran-2-one inhibitors of cholesterol synthesis
US5397792A (en) * 1993-03-03 1995-03-14 Warner-Lambert Company Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
US5446054A (en) * 1993-03-03 1995-08-29 Warner-Lambert Company Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
AU677047B2 (en) * 1993-03-03 1997-04-10 Warner-Lambert Company Novel process for (trans)-6-(2-(substituted-pyrrol-1-YL) alkyl)pyran-2-one inhibitors of cholesterol synthesis
WO1994020492A1 (en) * 1993-03-03 1994-09-15 Warner-Lambert Company Novel process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
US5342952A (en) * 1993-03-03 1994-08-30 Warner-Lambert Company Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
US5470981A (en) * 1993-03-03 1995-11-28 Warner-Lambert Company Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
US5298627A (en) * 1993-03-03 1994-03-29 Warner-Lambert Company Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
EP1743630A2 (en) 1997-07-31 2007-01-17 Kos Pharmaceuticals, Inc. Pharmaceutical combination
EP1743644A1 (en) 1997-07-31 2007-01-17 Kos Pharmaceuticals, Inc. Combinations of hmg-coa reductase inhibitors and nicotinic acid and methods for treating hyperlipidemia
US6177121B1 (en) 1997-09-29 2001-01-23 Purdue Research Foundation Composition and method for producing low cholesterol eggs
US20060141035A1 (en) * 1997-12-12 2006-06-29 Andrx Labs Llc HMG-COA reductase inhibitor extended release formulation
US8679534B2 (en) 1997-12-12 2014-03-25 Andrx Labs, Llc HMG-CoA reductase inhibitor extended release formulation
US20110027371A1 (en) * 1998-10-01 2011-02-03 Elan Pharma International Limited Nanoparticulate statin formulations and novel statin combinations
US20080213378A1 (en) * 1998-10-01 2008-09-04 Elan Pharma International, Ltd. Nanoparticulate statin formulations and novel statin combinations
WO2000028981A3 (en) * 1998-11-13 2000-11-09 Nymox Corp Methods for treating, preventing, and reducing the risk of the onset of alzheimer's disease using an hmg coa reductase inhibitor
US20070253905A1 (en) * 2000-04-13 2007-11-01 Mayo Foundation For Medical Education Abeta42 LOWERING AGENTS
US20060166999A1 (en) * 2000-06-21 2006-07-27 Bayer Aktiengesellschaft Use of microsomal triglyceride transfer protein (MTP) inhibitors for reducing the number of postprandial triglyceride-rich lipoprotein particles (PPTRL)
US20080125412A1 (en) * 2000-09-04 2008-05-29 Lieven Meerpoel Polyarylcarboxamides useful as lipid lowering agents
US8354402B2 (en) 2000-09-04 2013-01-15 Janssen Pharmaceutica N.V. Polyarylcarboxamides useful as lipid lowering agents
US20080241070A1 (en) * 2000-09-21 2008-10-02 Elan Pharma International Ltd. Fenofibrate dosage forms
US20040102490A1 (en) * 2000-11-21 2004-05-27 Lieven Meerpoel Biphenylcarboxamides useful as lipid lowering agents
US7244848B2 (en) 2000-11-21 2007-07-17 Janssen Pharmaceutica N.V. Biphenylcarboxamides useful as lipid lowering agents
US7304167B2 (en) 2000-11-21 2007-12-04 Janssen Pharmaceutica N.V. Biphenylcarboxamides useful as lipid lowering agents
US7135586B2 (en) 2000-11-21 2006-11-14 Janssen Pharmaceutica, Nv Biphenylcarboxamides useful as lipid lowering agents
US20060128972A1 (en) * 2000-11-21 2006-06-15 Lieven Meerpoel Biphenylcarboxamides useful as lipid lowering agents
US20080275087A1 (en) * 2000-11-21 2008-11-06 Lieven Meerpoel Biphenylcarboxamides useful as lipid lowering agents
US7538124B2 (en) 2000-11-21 2009-05-26 Janssen Pharmaceutica N.V. Biphenylcarboxamides useful as lipid lowering agents
US7405307B2 (en) 2000-11-21 2008-07-29 Janssen Pharmaceutica N.V. Biphenylcarboxamides useful as lipid lowering agents
US7642378B2 (en) 2001-04-06 2010-01-05 Janssen Pharmaceutica Nv Lipid lowering biphenylcarboxamides
US20080081813A1 (en) * 2001-04-06 2008-04-03 Lieven Meerpoel Lipid Lowering Biphenylcarboxamides
US6774112B2 (en) 2001-04-11 2004-08-10 Bristol-Myers Squibb Company Amino acid complexes of C-aryl glucosides for treatment of diabetes and method
US20060194772A1 (en) * 2001-06-28 2006-08-31 Pfizer Inc Triamide-substituted heterobicyclic compounds
US7348355B2 (en) * 2001-06-28 2008-03-25 Pfizer Inc. Triamide-substituted heterobicyclic compounds
US20040254391A1 (en) * 2001-07-03 2004-12-16 Blacker Andrew John Process for the preparation of nitrile compounds
US20100210552A1 (en) * 2001-10-18 2010-08-19 Bristol-Myers Squibb Company Human glucagon-like peptide-1 mimics and their use in the treatment of diabetes and related conditions
US20070287670A1 (en) * 2001-10-18 2007-12-13 Bristol-Myers Squibb Company Human glucagon-like peptide-1 mimics and their use in the treatment of diabetes and related conditions
US20040127423A1 (en) * 2001-10-18 2004-07-01 Natarajan Sesha Iyer Human glucagon-like-peptide-1 mimics and their use in the treatment of diabetes and related conditions
US7238671B2 (en) 2001-10-18 2007-07-03 Bristol-Myers Squibb Company Human glucagon-like-peptide-1 mimics and their use in the treatment of diabetes and related conditions
US20030195157A1 (en) * 2001-10-18 2003-10-16 Natarajan Sesha Iyer Human glucagon-like-peptide-1 mimics and their use in the treatment of diabetes and related conditions
US7238670B2 (en) 2001-10-18 2007-07-03 Bristol-Myers Squibb Company Human glucagon-like-peptide-1 mimics and their use in the treatment of diabetes and related conditions
US20030157671A1 (en) * 2001-11-02 2003-08-21 Ramakrishnan Chidambaram Process for the preparation of aniline-derived thyroid receptor ligands
US7956214B2 (en) 2001-11-02 2011-06-07 Karo Bio Ab Process for the preparation of aniline-derived thyroid receptor ligands
US20050054873A1 (en) * 2001-11-02 2005-03-10 Ramakrishnan Chidambaram Process for the preparation of aniline-derived thyroid receptor ligands
US20090326263A1 (en) * 2001-11-02 2009-12-31 Ramakrishnan Chidambaram Process for the preparation of aniline-derived thyroid receptor ligands
US6806381B2 (en) 2001-11-02 2004-10-19 Bristol-Myers Squibb Company Process for the preparation of aniline-derived thyroid receptor ligands
US6984645B2 (en) 2001-11-16 2006-01-10 Bristol-Myers Squibb Company Dual inhibitors of adipocyte fatty acid binding protein and keratinocyte fatty acid binding protein
US20030225091A1 (en) * 2001-11-16 2003-12-04 Magnin David R. Dual inhibitors of adipocyte fatty acid binding protein and keratinocyte fatty acid binding protein
US6951844B2 (en) 2001-12-07 2005-10-04 Bristol Myers Squibb Company Phenyl naphthol ligands for thyroid hormone receptor
US20030166724A1 (en) * 2001-12-07 2003-09-04 Hangeland Jon J. Phenyl naphthol ligands for thyroid hormone receptor
US6831102B2 (en) 2001-12-07 2004-12-14 Bristol-Myers Squibb Company Phenyl naphthol ligands for thyroid hormone receptor
US20050054727A1 (en) * 2001-12-07 2005-03-10 Hangeland Jon J. Phenyl naphthol ligands for thyroid hormone receptor
US20050038122A1 (en) * 2001-12-07 2005-02-17 Hangeland Jon J. Phenyl naphthol ligands for thyroid hormone receptor
US6747048B2 (en) 2002-05-08 2004-06-08 Bristol-Myers Squibb Company Pyridine-based thyroid receptor ligands
US20040002495A1 (en) * 2002-05-20 2004-01-01 Philip Sher Lactam glycogen phosphorylase inhibitors and method of use
US20060128687A1 (en) * 2002-05-20 2006-06-15 Philip Sher Lactam glycogen phosphorylase inhibitors and method of use
US7425550B2 (en) 2002-05-20 2008-09-16 Bristol-Meyers Squibb Company Lactam glycogen phosphorylase inhibitors and method of use
US7057046B2 (en) 2002-05-20 2006-06-06 Bristol-Myers Squibb Company Lactam glycogen phosphorylase inhibitors and method of use
US20040058009A1 (en) * 2002-05-24 2004-03-25 Elan Pharma International, Ltd. Nanoparticulate fibrate formulations
US20050276974A1 (en) * 2002-05-24 2005-12-15 Elan Pharma Internationl, Ltd. Nanoparticulate fibrate formulations
US7931917B2 (en) 2002-05-24 2011-04-26 Elan Pharma International, Ltd. Nanoparticulate fibrate formulations
US20080138424A1 (en) * 2002-05-24 2008-06-12 Elan Pharma Internationa, Ltd. Nanoparticulate fibrate formulations
US20080095851A1 (en) * 2002-05-24 2008-04-24 Elan Pharma International, Ltd. Nanoparticulate fibrate formulations
US20070298115A1 (en) * 2002-05-24 2007-12-27 Elan Pharma International, Ltd. Nanoparticulate fibrate formulations
US7927627B2 (en) 2002-05-24 2011-04-19 Elan Pharma International, Ltd. Nanoparticulate fibrate formulations
US7320802B2 (en) 2002-05-24 2008-01-22 Elan Pharma International, Ltd. Methods of treatment using nanoparticulate fenofibrate compositions
US7276249B2 (en) 2002-05-24 2007-10-02 Elan Pharma International, Ltd. Nanoparticulate fibrate formulations
US20030224058A1 (en) * 2002-05-24 2003-12-04 Elan Pharma International, Ltd. Nanoparticulate fibrate formulations
US20040087656A1 (en) * 2002-05-24 2004-05-06 Elan Pharma International, Ltd. Nanoparticulate fibrate formulations
US20070264348A1 (en) * 2002-05-24 2007-11-15 Elan Pharma International, Ltd. Nanoparticulate fibrate formulations
US20100143962A1 (en) * 2002-06-10 2010-06-10 Elan Pharma International Ltd. Nanoparticulate polycosanol formulations & novel polycosanol combinations
US7763278B2 (en) 2002-06-10 2010-07-27 Elan Pharma International Ltd. Nanoparticulate polycosanol formulations and novel polycosanol combinations
US20030232796A1 (en) * 2002-06-10 2003-12-18 Elan Pharma International, Ltd. Nanoparticulate polycosanol formulations & novel polycosanol combinations
US20090156623A1 (en) * 2002-08-12 2009-06-18 Lieven Meerpoel N-aryl piperidine substituted biphenylcarboxamides
US8258304B2 (en) 2002-08-12 2012-09-04 Janssen Pharmaceutica N.V. N-aryl piperidine substituted biphenylcarboxamides
US20060019269A1 (en) * 2002-10-17 2006-01-26 Decode Genetics, Inc. Susceptibility gene for myocardial infarction, stroke, and PAOD, methods of treatment
US20080293750A1 (en) * 2002-10-17 2008-11-27 Anna Helgadottir Susceptibility Gene for Myocardial Infarction, Stroke, Paod and Methods of Treatment
US20040259919A1 (en) * 2002-10-23 2004-12-23 Magnin David R. Glycinenitrile-based inhibitors of dipeptidyl peptidase IV and methods
US6995180B2 (en) 2002-10-23 2006-02-07 Bristol Myers Squibb Company Glycinenitrile-based inhibitors of dipeptidyl peptidase IV and methods
US7098235B2 (en) 2002-11-14 2006-08-29 Bristol-Myers Squibb Co. Triglyceride and triglyceride-like prodrugs of glycogen phosphorylase inhibiting compounds
US20040142938A1 (en) * 2002-11-14 2004-07-22 Sher Philip M. Triglyceride and triglyceride-like prodrugs of glycogen phosphorylase inhibiting compounds
US20040132771A1 (en) * 2002-12-20 2004-07-08 Pfizer Inc Compositions of choleseteryl ester transfer protein inhibitors and HMG-CoA reductase inhibitors
EP1961419A1 (en) 2002-12-20 2008-08-27 Pfizer Products Inc. Dosage forms comprising a CETP inhibitor and an HMG-CoA reductase inhibitor
US20040180940A1 (en) * 2003-01-24 2004-09-16 Washburn William N. Substituted anilide ligands for the thyroid receptor
US7342127B2 (en) 2003-01-24 2008-03-11 Bristol-Myers Squibb Company Substituted anilide ligands for the thyroid receptor
US20040176425A1 (en) * 2003-01-24 2004-09-09 Washburn William N. Cycloalkyl containing anilide ligands for the thyroid receptor
US20050288375A1 (en) * 2003-02-05 2005-12-29 Myriad Genetics, Incorporated Method and composition for treating neurodegenerative disorders
US20050004184A1 (en) * 2003-04-18 2005-01-06 Ryono Denis E. Thyroid receptor ligands
US8263659B2 (en) 2003-04-18 2012-09-11 Bristol-Myers Squibb Company Thyroid receptor ligands
US20100298276A1 (en) * 2003-04-18 2010-11-25 Bristol-Myers Squibb Company Thyroid receptor ligands
US7557143B2 (en) 2003-04-18 2009-07-07 Bristol-Myers Squibb Company Thyroid receptor ligands
US7323490B2 (en) 2003-05-16 2008-01-29 Ambit Biosciences Corporation Pyrrole compounds and uses thereof
US20040242673A1 (en) * 2003-05-16 2004-12-02 Ambit Biosciences Corporation Heterocyclic compounds and uses thereof
US20050182125A1 (en) * 2003-05-16 2005-08-18 Ambit Biosciences Corporation Pyrrole compounds and uses thereof
US20040248972A1 (en) * 2003-05-16 2004-12-09 Ambit Biosciences Corporation Compounds and uses thereof
US20040248957A1 (en) * 2003-05-16 2004-12-09 Ambit Biosciences Corporation Heterocyclic compounds and uses thereof
US20040259880A1 (en) * 2003-05-16 2004-12-23 Ambit Biosciences Corporation Pyrrole compounds and uses thereof
US20040266831A1 (en) * 2003-06-11 2004-12-30 Robinson Leslie A. Modulators of the glucocorticoid receptor and method
US7459474B2 (en) 2003-06-11 2008-12-02 Bristol-Myers Squibb Company Modulators of the glucocorticoid receptor and method
US20050042284A1 (en) * 2003-07-11 2005-02-24 Myriad Genetics, Incorporated Pharmaceutical methods, dosing regimes and dosage forms for the treatment of Alzheimer's disease
US20050038020A1 (en) * 2003-08-01 2005-02-17 Hamann Lawrence G. Adamantylglycine-based inhibitors of dipeptidyl peptidase IV and methods
EP1997489A1 (en) 2003-08-01 2008-12-03 Bristol-Myers Squibb Company Adamantylglycine derivatives as inhibitors of dipeptidyl peptidase IV for the treatment of diabetes
US20050228021A1 (en) * 2003-08-01 2005-10-13 Hamann Lawrence G Adamantylglycine-based inhibitors of dipeptidyl peptidase IV and methods
US20050239839A1 (en) * 2003-08-01 2005-10-27 Hamann Lawrence G Adamantylglycine-based inhibitors of dipeptidyl peptidase IV and methods
US6995183B2 (en) 2003-08-01 2006-02-07 Bristol Myers Squibb Company Adamantylglycine-based inhibitors of dipeptidyl peptidase IV and methods
US20050171207A1 (en) * 2003-09-26 2005-08-04 Myriad Genetics, Incorporated Method and composition for combination treatment of neurodegenerative disorders
EP2428516A1 (en) 2003-11-19 2012-03-14 Metabasis Therapeutics, Inc. Novel phosphorus-containing thyromimetics
US20080020046A1 (en) * 2004-01-23 2008-01-24 Fournier Laboratories Ireland Limited Pharmaceutical Formulations Comprising Metformin And A Fibrate, And Processes For Obtaining Them
US20100216863A1 (en) * 2004-01-30 2010-08-26 Decode Genetics Ehf. Susceptibility Gene for Myocardial Infarction, Stroke, and PAOD; Methods of Treatment
US10555938B2 (en) 2004-03-05 2020-02-11 The Trustees Of The University Of Pennsylvania Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side effects
US9861622B2 (en) 2004-03-05 2018-01-09 The Trustees Of The University Of Pennsylvania Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side-effects
WO2005087234A1 (en) 2004-03-05 2005-09-22 The Trustees Of The University Of Pennsylvania Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side-effects
US20090042941A1 (en) * 2004-03-05 2009-02-12 Rader Daniel J Methods for Treating Disorders or Diseases Associated with Hyperlipidemia and Hypercholesterolemia While Minimizing Side Effects
US8618135B2 (en) 2004-03-05 2013-12-31 The Trustees Of The University Of Pennsylvania Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side effects
US9265758B2 (en) 2004-03-05 2016-02-23 The Trustees Of The University Of Pennsylvania Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side-effects
US7932268B2 (en) 2004-03-05 2011-04-26 The Trustees Of The University Of Pennsylvania Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side effects
US9364470B2 (en) 2004-03-05 2016-06-14 The Trustees Of The University Of Pennsylvania Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side-effects
US11554113B2 (en) 2004-03-05 2023-01-17 The Trustees Of The University Of Pennsylvania Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side-effects
US9433617B1 (en) 2004-03-05 2016-09-06 The Trustees Of The University Of Pennsylvania Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side-effects
US10016404B2 (en) 2004-03-05 2018-07-10 The Trustees Of The University Of Pennsylvania Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side effects
US20070293538A1 (en) * 2004-04-13 2007-12-20 Myriad Genetics, Incorporated Pharmaceutical Composition And Methods For Treating Neurodegenerative Disorders
US20050252144A1 (en) * 2004-04-29 2005-11-17 Macdonald Robert A Veneers for walls, retaining walls and the like
US20060004222A1 (en) * 2004-07-02 2006-01-05 Arvind Mathur Process for the preparation of amino acids useful in the preparation of peptide receptor modulators
US7145040B2 (en) 2004-07-02 2006-12-05 Bristol-Myers Squibb Co. Process for the preparation of amino acids useful in the preparation of peptide receptor modulators
US20080242593A1 (en) * 2004-07-02 2008-10-02 Bristol-Myers Squibb Company Human glucagon-like-peptide-1 modulators and their use in the treatment of diabetes and related conditions
US7534763B2 (en) 2004-07-02 2009-05-19 Bristol-Myers Squibb Company Sustained release GLP-1 receptor modulators
US7417028B2 (en) 2004-07-02 2008-08-26 Bristol-Myers Squibb Company Human glucagon-like-peptide-1 modulators and their use in treatment of diabetes and related conditions
US20060287242A1 (en) * 2004-07-02 2006-12-21 Ewing William R Human glucagon-like-peptide-1 modulators and their use in treatment of diabetes and related conditions
US20070232672A1 (en) * 2004-08-11 2007-10-04 Myriad Genetics, Incorporated Pharmaceutical Composition And Method For Treating Neurodegenerative Disorders
US20070232656A1 (en) * 2004-08-11 2007-10-04 Myriad Genetics, Incorporated Pharmaceutical Composition And Method For Treating Neurodegenerative Disorders
US20070232589A1 (en) * 2004-08-11 2007-10-04 Myriad Genetics, Incorporated Pharmaceutical Composition And Method For Treating Neurodegenerative Disorders
US20060063722A1 (en) * 2004-09-23 2006-03-23 William Washburn C-aryl glucoside SGLT2 inhibitors and method
US7589193B2 (en) 2004-09-23 2009-09-15 Bristol-Myers Squibb Company C-aryl glucoside SGLT2 inhibitors and method
US7517991B2 (en) 2004-10-12 2009-04-14 Bristol-Myers Squibb Company N-sulfonylpiperidine cannabinoid receptor 1 antagonists
US20060079556A1 (en) * 2004-10-12 2006-04-13 Sher Philip M N-sulfonylpiperidine cannabinoid receptor 1 antagonists
US20060178377A1 (en) * 2004-12-29 2006-08-10 Wei Meng Azolopyrimidine-based inhibitors of dipeptidyl peptidase IV and methods
US7589088B2 (en) 2004-12-29 2009-09-15 Bristol-Myers Squibb Company Pyrimidine-based inhibitors of dipeptidyl peptidase IV and methods
US20060142576A1 (en) * 2004-12-29 2006-06-29 Wei Meng Pyrimidine-based inhibitors of dipeptidyl peptidase IV and methods
US7635699B2 (en) 2004-12-29 2009-12-22 Bristol-Myers Squibb Company Azolopyrimidine-based inhibitors of dipeptidyl peptidase IV and methods
US20060155126A1 (en) * 2005-01-12 2006-07-13 Chongqing Sun Bicyclic heterocycles as cannabinoid receptor modulators
US7361766B2 (en) 2005-01-12 2008-04-22 Bristol-Myers Squibb Company Bicyclic heterocycles as cannabinoid receptor modulators
US20060154955A1 (en) * 2005-01-12 2006-07-13 Chongqing Sun Bicyclic heterocycles as cannabinoid receptor modulators
US7314882B2 (en) 2005-01-12 2008-01-01 Bristol-Myers Squibb Company Bicyclic heterocycles as cannabinoid receptor modulators
US7368458B2 (en) 2005-01-12 2008-05-06 Bristol-Myers Squibb Company Bicyclic heterocycles as cannabinoid receptor modulators
US7220859B2 (en) 2005-01-12 2007-05-22 Bristol-Myers Squibb Company Bicyclic heterocycles as cannabinoid receptor modulators
US7709647B2 (en) 2005-01-18 2010-05-04 Bristol-Myers Squibb Company Tetrahydroquinoline cannabinoid receptor modulators
US20080200459A1 (en) * 2005-01-18 2008-08-21 Bristol-Myers Squibb Company Tetrahydroquinoline cannabinoid receptor modulators
US20070280917A1 (en) * 2005-03-30 2007-12-06 Decode Genetics, Inc. Susceptibility gene for myocardial infarction, stroke, and PAOD; methods of treatment
US8158362B2 (en) 2005-03-30 2012-04-17 Decode Genetics Ehf. Methods of diagnosing susceptibility to myocardial infarction and screening for an LTA4H haplotype
EP2527337A1 (en) 2005-04-14 2012-11-28 Bristol-Myers Squibb Company Inhibitors of 11-beta hydroxysteroid dehydrogenase type I
US7521557B2 (en) 2005-05-20 2009-04-21 Bristol-Myers Squibb Company Pyrrolopyridine-based inhibitors of dipeptidyl peptidase IV and methods
US20070021346A1 (en) * 2005-05-26 2007-01-25 Ewing William R N-terminally modified GLP-1 receptor modulators
US20060287342A1 (en) * 2005-06-17 2006-12-21 Mikkilineni Amarendra B Triazolopyrimidine heterocycles as cannabinoid receptor modulators
US20100048612A1 (en) * 2005-06-17 2010-02-25 Bristol-Myers Squibb Company Bicyclic heterocycles as cannabinoid-1 receptor modulators
US7452892B2 (en) 2005-06-17 2008-11-18 Bristol-Myers Squibb Company Triazolopyrimidine cannabinoid receptor 1 antagonists
US7572808B2 (en) 2005-06-17 2009-08-11 Bristol-Myers Squibb Company Triazolopyridine cannabinoid receptor 1 antagonists
US20070004772A1 (en) * 2005-06-17 2007-01-04 Chongqing Sun Triazolopyridine cannabinoid receptor 1 antagonists
US20060287341A1 (en) * 2005-06-17 2006-12-21 Gang Wu Triazolopyrimidine cannabinoid receptor 1 antagonists
US20060287324A1 (en) * 2005-06-17 2006-12-21 Chongqing Sun Bicyclic heterocycles as cannabinoid-1 receptor modulators
US20060287322A1 (en) * 2005-06-17 2006-12-21 Chongqing Sun Bicyclic heterocycles as cannabinoind-1 receptor modulators
US20060287323A1 (en) * 2005-06-17 2006-12-21 Ewing William R Azabicyclic heterocycles as cannabinoid receptor modulators
US7629342B2 (en) 2005-06-17 2009-12-08 Bristol-Myers Squibb Company Azabicyclic heterocycles as cannabinoid receptor modulators
US7632837B2 (en) 2005-06-17 2009-12-15 Bristol-Myers Squibb Company Bicyclic heterocycles as cannabinoid-1 receptor modulators
US7317012B2 (en) 2005-06-17 2008-01-08 Bristol-Myers Squibb Company Bicyclic heterocycles as cannabinoind-1 receptor modulators
US7858639B2 (en) 2005-06-17 2010-12-28 Bristol-Myers Squibb Company Bicyclic heterocycles as cannabinoid-1 receptor modulators
US20070015832A1 (en) * 2005-07-14 2007-01-18 Myriad Genetics, Incorporated Methods of treating overactive bladder and urinary incontinence
US20070042034A1 (en) * 2005-07-22 2007-02-22 Myriad Genetics, Incorporated High drug load formulations and dosage forms
US20080139457A1 (en) * 2005-09-16 2008-06-12 Virginia Commonwealth University Therapeutic compositions comprising chorionic gonadotropins and HMG CoA reductase inhibitors
US20070088089A1 (en) * 2005-10-18 2007-04-19 Wisler Gerald L Methods for treating disorders associated with hyperlipidemia in a mammal
US20070093527A1 (en) * 2005-10-18 2007-04-26 Wisler Gerald L Methods for treating disorders associated with hyperlipidemia in a mammal
US20070093468A1 (en) * 2005-10-18 2007-04-26 Wisler Gerald L Methods for treating disorders associated with hyperlipidemia in a mammal
EP2298776A1 (en) 2005-10-26 2011-03-23 Bristol-Myers Squibb Company Thienopyrimidinone derivatives as melanin concentrating hormone receptor-1 antagonists
US20070093509A1 (en) * 2005-10-26 2007-04-26 Bristol-Myers Squibb Company Non-basic melanin concentrating hormone receptor-1 antagonists
US8618115B2 (en) 2005-10-26 2013-12-31 Bristol-Myers Squibb Company Substituted thieno[3,2-d]pyrimidinones as MCHR1 antagonists and methods for using them
WO2007053819A2 (en) 2005-10-31 2007-05-10 Bristol-Myers Squibb Company Pyrrolidinyl beta-amino amide-based inhibitors of dipeptidyl peptidase iv and methods
EP2487154A1 (en) 2005-10-31 2012-08-15 Bristol-Myers Squibb Company Pyrrolidinyl beta-amino amide-based inhibitors of dipeptidyl peptidase IV and methods
WO2007073503A2 (en) 2005-12-21 2007-06-28 Bristol-Myers Squibb Company Indane modulators of glucocorticoid receptor, ap-1, and/or nf-kb activity and use thereof
US20070238669A1 (en) * 2006-01-11 2007-10-11 Bristol-Myers Squibb Company Human glucagon-like-peptide-1 modulators and their use in the treatment of diabetes related conditions
US20070185097A1 (en) * 2006-02-06 2007-08-09 Bristol-Myers Squibb Company Melanin concentrating hormone receptor-1 antagonists
US20090221548A1 (en) * 2006-02-06 2009-09-03 Bristol-Myers Squibb Company Melanin concentrating hormone receptor-1 antagonists
US7956049B2 (en) 2006-02-06 2011-06-07 Bristol-Myers Squibb Company Melanin concentrating hormone receptor-1 antagonists
US7553836B2 (en) 2006-02-06 2009-06-30 Bristol-Myers Squibb Company Melanin concentrating hormone receptor-1 antagonists
US20090069275A1 (en) * 2006-02-17 2009-03-12 Rocca Jose G Low flush niacin formulation
US20070202180A1 (en) * 2006-02-28 2007-08-30 Elan Pharma International Limited Nanoparticulate carverdilol formulations
US8367112B2 (en) 2006-02-28 2013-02-05 Alkermes Pharma Ireland Limited Nanoparticulate carverdilol formulations
US20070238770A1 (en) * 2006-04-05 2007-10-11 Bristol-Myers Squibb Company Process for preparing novel crystalline forms of peliglitazar, novel stable forms produced therein and formulations
WO2007140191A2 (en) 2006-05-23 2007-12-06 Theracos, Inc. Glucose transport inhibitors and methods of use
US7960349B2 (en) 2006-05-26 2011-06-14 Bristol-Myers Squibb Company N-terminally modified GLP-1 receptor modulators
WO2007139589A1 (en) 2006-05-26 2007-12-06 Bristol-Myers Squibb Company Sustained release glp-1 receptor modulators
US20100022457A1 (en) * 2006-05-26 2010-01-28 Bristol-Myers Squibb Company Sustained release glp-1 receptor modulators
US20080045461A1 (en) * 2006-05-26 2008-02-21 Bristol-Myers Squibb Company N-terminally modified glp-1 receptor modulators
EP3363807A1 (en) 2006-06-28 2018-08-22 AstraZeneca AB Pharmaceutical composition comprising crystalline (2s,3r,4s,5s,6r)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4,5-triol (s)-propylene glycol solvate
EP3045466A1 (en) 2006-06-28 2016-07-20 AstraZeneca AB (2s,3r,4s,5s,6r)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4,5-triol propylene glycol solvate as sgt2 inhibitor for the treatment of diabetes
EP2457918A2 (en) 2006-06-28 2012-05-30 Bristol-Myers Squibb Company Crystalline solvates and complexes of (1s)-1,5-anhydro-1-c-(3-((phenyl) methyl) phenyl)-d-glucitol derivatives with amino acids as SGLT2 inhibitors for the treatment of diabetes
US20080044326A1 (en) * 2006-07-04 2008-02-21 Esencia Co., Ltd. Sterilizer for baby products
WO2008006043A2 (en) 2006-07-07 2008-01-10 Bristol-Myers Squibb Company 1,3-oxazole derivatives useful as anti-atherosclerotic, anti-dyslipidemic, anti-diabetic and anti-obesity agents
US20080033045A1 (en) * 2006-07-07 2008-02-07 Myriad Genetics, Incorporated Treatment of psychiatric disorders
WO2008057862A2 (en) 2006-11-01 2008-05-15 Bristol-Myers Squibb Company MODULATORS OF GLUCOCORTICOID RECEPTOR, AP-1, AND/OR NF-&kappav;B ACTIVITY AND USE THEREOF
US20080161279A1 (en) * 2006-12-21 2008-07-03 Wisler Gerald L Methods of Treating Obesity
US20090326013A1 (en) * 2007-03-01 2009-12-31 Curt Hendrix Isomers of inositol niacinate and uses thereof
EP4245299A2 (en) 2007-03-22 2023-09-20 Astrazeneca AB Pharmaceutical formulations containing dapagliflozin propylene glycol hydrate
US8802715B2 (en) 2007-04-20 2014-08-12 Astrazeneca Ab Crystal forms of saxagliptin and processes for preparing same
US7943656B2 (en) 2007-04-20 2011-05-17 Bristol-Myers Squibb Company Crystal forms of saxagliptin and processes for preparing same
EP2481726A2 (en) 2007-04-20 2012-08-01 Bristol-Myers Squibb Company Crystal forms of saxagliptin and processes for preparing same
US8236847B2 (en) 2007-04-20 2012-08-07 Bristol-Myers Squibb Company Crystal forms of saxagliptin and processes for preparing same
US20090054303A1 (en) * 2007-04-20 2009-02-26 Bristol-Myers Squibb Company Crystal forms of saxagliptin and processes for preparing same
US20080287529A1 (en) * 2007-05-18 2008-11-20 Bristol-Myers Squibb Company Crystal structures of sglt2 inhibitors and processes for preparing same
EP2572712A2 (en) 2007-06-01 2013-03-27 The Trustees Of Princeton University Treatment of viral infections by modulation of host cell metabolic pathways
US9029413B2 (en) 2007-06-01 2015-05-12 The Trustees Of Princeton University Treatment of viral infections by modulation of host cell metabolic pathways
EP2581081A2 (en) 2007-06-01 2013-04-17 The Trustees Of Princeton University Treatment of viral infections by modulation of host cell metabolic pathways
US8158677B2 (en) 2007-06-01 2012-04-17 The Trustees Of Princeton University Treatment of viral infections by modulation of host cell metabolic pathways
US9757407B2 (en) 2007-06-01 2017-09-12 The Trustees Of Princeton University Treatment of viral infections by modulation of host cell metabolic pathways
US8067420B2 (en) 2007-07-06 2011-11-29 Bristol-Myers Squibb Company Substituted pyrazinone melanin concentrating hormone receptor-1 antagonists and methods
US20110144060A1 (en) * 2007-07-06 2011-06-16 Bristol-Myers Squibb Company Substituted pyrazinone melanin concentrating hormone receptor-1 antagonists and methods
US20110003759A1 (en) * 2007-07-06 2011-01-06 Bristol-Myers Squibb Company Non-basic melanin concentrating hormone receptor-1 antagonists and methods
US8012984B2 (en) 2007-07-06 2011-09-06 Bristol-Myers Squibb Company Substituted pyrazinone melanin concentrating hormone receptor-1 antagonists and methods
US20100324071A1 (en) * 2007-07-27 2010-12-23 Bristol-Myers Squibb Company Novel glucokinase activators and methods of using same
US7812048B2 (en) 2007-07-27 2010-10-12 Bristol-Myers Squibb Company Glucokinase activators and methods of using same
US20090030046A1 (en) * 2007-07-27 2009-01-29 Bristol-Myers Squibb Company Novel glucokinase activators and methods of using same
US8273777B2 (en) 2007-07-27 2012-09-25 Bristol-Meyer Squibb Company Glucokinase activators and methods of using same
EP3318562A2 (en) 2007-08-23 2018-05-09 Theracos Sub, LLC Benzylbenzene derivatives and methods of use
US8258156B2 (en) 2007-09-20 2012-09-04 Irm Llc Compounds and compositions as modulators of GPR119 activity
US8153635B2 (en) 2007-09-20 2012-04-10 Irm Llc Compounds and compositions as modulators of GPR119 activity
US20110224185A1 (en) * 2007-09-20 2011-09-15 IRM LLC, a Delaware Limited Company Compounds and compositions as modulators of gpr119 activity
US20090270409A1 (en) * 2007-09-20 2009-10-29 Irm Llc Compounds and compositions as modulators of gpr119 activity
US20090298794A1 (en) * 2008-05-29 2009-12-03 Bristol-Myers Squibb Company Hydroxy substituted thieno pyrimidinones as melanin concentrating hormone receptor-1 antagonists
US7989433B2 (en) 2008-05-29 2011-08-02 Bristol-Myers Squibb Company Substituted thieno[3,2-D]pyrimidines as melanin concentrating hormone receptor-1 antagonists
WO2010009243A1 (en) 2008-07-15 2010-01-21 Theracos, Inc. Deuterated benzylbenzene derivatives and methods of use
WO2010093601A1 (en) 2009-02-10 2010-08-19 Metabasis Therapeutics, Inc. Novel sulfonic acid-containing thyromimetics, and methods for their use
WO2010111665A1 (en) 2009-03-27 2010-09-30 Bristol-Myers Squibb Company Methods for preventing major adverse cardiovascular events with dpp-iv inhibitors
WO2011014520A2 (en) 2009-07-29 2011-02-03 Irm Llc Compounds and compositions as modulators of gpr119 activity
WO2011044001A1 (en) 2009-10-09 2011-04-14 Irm Llc Compounds and compositions as modulators of gpr119 activity
WO2011060290A2 (en) 2009-11-13 2011-05-19 Bristol-Myer Squibb Company Immediate release tablet formulations
WO2011060256A2 (en) 2009-11-13 2011-05-19 Bristol-Myers Squibb Company Bilayer tablet formulations
WO2011060255A1 (en) 2009-11-13 2011-05-19 Bristol-Myers Squibb Company Reduced mass metformin formulations
EP3315124A1 (en) 2009-11-13 2018-05-02 Astrazeneca AB Bilayer tablet formulations
WO2011067306A1 (en) 2009-12-03 2011-06-09 Novartis Ag Cyclohexane derivatives as inhibitors of acetyl-coa carboxylase (acc)
WO2011109333A1 (en) 2010-03-02 2011-09-09 Lexicon Pharmaceuticals, Inc. 6 -benzylphenyl- 2 - sulfurterahydropyran-3, 4, 5 -triol derivatives as inhibitors of sodium -glucose cotrans porters 1 and 2 for use in diabetic patients
WO2011130459A1 (en) 2010-04-14 2011-10-20 Bristol-Myers Squibb Company Novel glucokinase activators and methods of using same
WO2011153953A1 (en) 2010-06-12 2011-12-15 Theracos, Inc. Crystalline form of benzylbenzene sglt2 inhibitor
WO2012006398A2 (en) 2010-07-09 2012-01-12 Bhv Pharma, Inc. Combination immediate/delayed release delivery system for short half-life pharmaceuticals including remogliflozin
WO2012013716A1 (en) 2010-07-29 2012-02-02 Novartis Ag Bicyclic acetyl-coa carboxylase inhibitors
WO2012094293A1 (en) 2011-01-05 2012-07-12 Lexicon Pharmaceuticals, Inc. Compositions comprising and methods of using inhibitors of sodium-glucose cotransporters 1 and 2
WO2014052619A1 (en) 2012-09-27 2014-04-03 Irm Llc Piperidine derivatives and compositions as modulators of gpr119 activity
EP3489226A1 (en) 2012-11-20 2019-05-29 Lexicon Pharmaceuticals, Inc. Inhibitors of sodium glucose cotransporter 1
WO2014081660A1 (en) 2012-11-20 2014-05-30 Lexicon Pharmaceuticals, Inc. Inhibitors of sodium glucose cotransporter 1
WO2015027021A1 (en) 2013-08-22 2015-02-26 Bristol-Myers Squibb Company Imide and acylurea derivatives as modulators of the glucocorticoid receptor
CN104356118A (en) * 2014-10-17 2015-02-18 上海应用技术学院 Polysubstitution pyrroles pitavastatin lactone dewatering compound and application thereof
WO2016176656A2 (en) 2015-04-30 2016-11-03 President And Fellows Of Harvard College Anti-ap2 antibodies and antigen binding agents to treat metabolic disorders
WO2020016335A1 (en) 2018-07-19 2020-01-23 Astrazeneca Ab Methods of treating hfpef employing dapagliflozin and compositions comprising the same
WO2020068661A1 (en) 2018-09-26 2020-04-02 Lexicon Pharmaceuticals, Inc. Crystalline forms of n-(1 -((2-(dimethylamino)ethyl)amino)-2-m ethyl-1 -oopropan-2-yl)-4-(4-(2-methyl-5- (2s,3r,4r,5s,6r)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2h-pyran-2-yl)benzyl) phenl)butanamide and methods of their synthesis

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